Diaminoalkane aspartic protease inhibitors

ABSTRACT

Diaminoalkanes of Formula I have now been found which are orally active and bind to aspartic proteases to inhibit their activity. They are useful in the treatment or amelioration of diseases associated with elevated levels of aspartic protease activity. The invention also relates to a method for the use of the compounds of Formula I in ameliorating or treating aspartic protease related disorders in a subject in need thereof comprising administering to said subject an effective amount of a compound of Formula I.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/664,558, filed Jan. 17, 2008 which is the U.S. National Stage ofInternational Application No. PCT/US2005/036230, filed Oct. 7, 2005,published in English, which claims the benefit of U.S. ProvisionalPatent Application No. 60/616,770, filed Oct. 7, 2004. The entireteachings of the above applications are incorporated herein byreference.

BACKGROUND

Aspartic proteases, including renin, (3-secretase (BACE), HIV protease,HTLV protease and plasmepsins I and II, are implicated in a number ofdisease states. In hypertension elevated levels of angiotensin I, theproduct of renin catalyzed cleavage of angioteninogen are present.Elevated levels of β amyloid, the product of BACE activity on amyloidprecursor protein, are widely believed to be responsible for the amyloidplaques present In the brains of Alzheimer's disease patients. Theviruses HIV and HTLV depend on their respective aspartic proteases forviral maturation. Plasmodium falciparum uses plasmepsins I and II todegrade hemoglobin.

In the renin-angiotensin-aldosterone system (RAAS) the biologicallyactive peptide angiotensin II (Ang II) is generated by a two-stepmechanism. The highly specific aspartic protease renin cleavesangiotensinogen to angiotensin I (Ang I), which is then furtherprocessed to Ang II by the less specific angiotensin-converting enzyme(ACE). Ang II is known to work on at least two receptor subtypes calledAT₁ and AT₂. Whereas AT₁ seems to transmit most of the known functionsof Ang II, the role of AT₂ is still unknown.

Modulation of the RAAS represents a major advance in the treatment ofcardiovascular diseases (Zaman, M. A. et al Nature Reviews DrugDiscovery 2002, 1, 621-636). ACE inhibitors and AT₁ blockers have beenaccepted as treatments of hypertension (Waeber B. et al., “Therenin-angiotensin system: role in experimental and human hypertension”,in Berkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam,Elsevier Science Publishing Co, 1996, 489-519; Weber M. A., Am. J.Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used forrenal protection (Rosenberg M. E. et al., Kidney International, 1994,45, 403; Breyer J. A. et al., Kidney International, 1994, 45, S156), inthe prevention of congestive heart failure (Vaughan D. E. et al.,Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med.,1988, 84 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. etal., N Engl. J: Med, 1992, 327, 669).

Interest in the development of renin inhibitors stems from thespecificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645).The only substrate known for renin is angiotensinogen, which can only beprocessed (under physiological conditions) by renin. In contrast, ACEcan also cleave bradykinin besides Ang I and can be bypassed by chymase,a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). Inpatients, inhibition of ACE thus leads to bradykinin accumulationcausing cough (5-20%) and potentially life-threatening angioneuroticedema (0.1-0.2%) (Israili Z. H. et al., Annals of Internal Medicine,1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore,the formation of Ang II is still possible in patients treated with ACEinhibitors. Blockade of the ATI receptor (e.g., by losartan) on theother hand overexposes other AT-receptor subtypes to Ang II, whoseconcentration is dramatically increased by the blockade of AT1receptors. In summary, renin inhibitors are not only expected to besuperior to ACE inhibitors and AT₁ blockers with regard to safety, butmore importantly also with regard to their efficacy in blocking theRAAS.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994,12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has beengenerated with renin inhibitors because their peptidomimetic characterimparts insufficient oral activity (Kleinert H. D., Cardiovasc. Drugs,1995, 9, 645). The clinical development of several compounds has beenstopped because of this problem together with the high cost of goods. Itappears as though only one compound has entered clinical trials (RahuelJ. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future,2001, 26, 1139). Thus, metabolically stable, orally bioavailable andsufficiently soluble renin inhibitors that can be prepared on a largescale are not available. Recently, the first non-peptide renininhibitors were described which show high in vitro activity (Oefner C.et al., Chem. Biol., 1999, 6, 127; Patent Application WO 97/09311;Maerki H. P. et al., Il Farmaco, 2001, 56, 21). The present inventionrelates to the unexpected identification of renin inhibitors of anon-peptidic nature and of low molecular weight. Orally active renininhibitors which are active in indications beyond blood pressureregulation where the tissular renin-chymase system may be activatedleading to pathophysiologically altered local functions such as renal,cardiac and vascular remodeling, atherosclerosis, and restenosis, aredescribed.

All documents cited herein are incorporated by reference.

SUMMARY OF THE INVENTION

Diaminoalkanes of Formula I have now been found which are orally activeand bind to aspartic proteases to inhibit their activity. They areuseful in the treatment or amelioration of diseases associated withaspartic protease activity.

The invention also relates to a method for the use of the compounds ofFormula I in ameliorating or treating aspartic protease relateddisorders in a subject in need thereof comprising administering to saidsubject an effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the invention provides compounds of Formula I

whereinR¹ is a) (C₁-C₁₂)alkyl, (C₃-C₇)cycloalkyl, (C₄-C₁₂)cycloalkylalkyl,halo(C₁-C₁₂)alkyl, halo(C₃-C₇)-cycloalkyl, halo(C₄-C₁₂)cycloalkylalkyl,saturated heterocyclyl optionally substituted with 1 to 5 groupsindependently selected from: halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,and oxo; or b) phenyl, napthyl, heteroaryl, or bicyclic heteroaryl eachoptionally substituted with 1 to 5 groups independently selected from:1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₃)alkyl(C₃-C₈)cycloalkyl,di(C₁-C₃)alkyl(C₃-C₈)cycloalkyl, (C₄-C₈)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₈)cycloalkenyl, (C₅-C₈)cyclo-alkylalkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₈)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₈)cycloalkylalkyl,(C₁-C₃)alkyl(C₄-C₈)cycloalkylalkyl,di(C₁-C₃)alkyl(C₄-C₈)cycloalkylalkyl, halo(C₂-C₈)alkenyl,halo(C₅-C₈)cycloalkenyl, halo(C₆-C₈)cycloalkenylalkyl,halo(C₃-C₈)alkynyl, halo(C₅-C₈)cycloalkylalkynyl, (C₁-C₈)alkoxy,(C₃-C₈)cycloalkoxy, (C₄-C₈)cycloalkylalkoxy,(C₁-C₃)alkyl(C₃-C₈)cycloalkoxy, (C₁-C₃)alkyl(C₄-C₈)cycloalkylalkoxy,di(C₁-C₃)alkyl(C₃-C₈)cycloalkoxy, di(C₁-C₃)alkyl(C₄-C₈)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₈)-cycloalkylalkoxy,(C₁-C₈)alkylthio, (C₃-C₈)cycloalkythio, (C₄-C₈)cycloalkylalkylthio,(C₁-C₃)alkyl(C₃-C₈)cycloalkythio,(C₁-C₃)alkyl(C₄-C₈)cycloalkylalkylthio,di(C₁-C₃)alkyl(C₃-C₈)cycloalkythio,di(C₁-C₃)alkyl(C₄-C₈)cycloalkylalkylthio, halo(C₁-C₈)alkylthio,halo(C₃-C₈)cycloalkythio, halo(C₄-C₈)-cycloalkylalkylthio,(C₁-C₈)alkanesulfinyl, (C₃-C₈)-cycloalkanesulfinyl,(C₄-C₈)cycloalkyl-alkanesulfinyl,(C₁-C₃)alkyl(C₃-C₈)cycloalkane-sulfinyl, (C₁-C₃)alkyl(C₄-C₈)cycloalkyl-alkanesulfinyl,di(C₁-C₃)alkyl(C₃-C₈)cycloalkane-sulfinyl, di(C₁-C₃)alkyl(C₄-C₈)cycloalkyl-alkanesulfinyl, halo(C₁-C₈)alkanesulfinyl,halo(C₃-C₈)cycloalkanesulfinyl, halo(C₄-C₈)cycloalkylalkanesulfinyl,(C₁-C₈)alkane-sulfonyl, (C₃-C₈)cycloalkanesulfonyl, (C₄-C₈)cycloalkylalkanesulfonyl, (C₁-C₃)alkyl(C₃-C₈)cycloalkanesulfonyl,(C₁-C₃)alkyl (C₄-C₈)cycloalkyl-alkanesulfonyl,di(C₁-C₃)alkyl(C₃-C₈)cycloalkanesulfonyl, di(C₁-C₃)alkyl(C₄-C₈)cycloalkyl-alkanesulfonyl, halo(C₁-C₈)alkanesulfonyl,halo(C₃-C₈)cycloalkanesulfonyl, halo(C₄-C₈)cycloalkylalkane-sulfonyl,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₈)alkoxycarbonyl, aminocarbonyl,(C₁-C₈)alkylamino-carbonyl, di(C₁-C₈)alkylaminocarbonyl, piperidino,pyrrolidino, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, (C₁-C₈)alkoxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkoxy(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)acylamino(C₁-C₆)alkyl,piperidino(C₁-C₆)alkyl and pyrrolidino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; or2) phenyl, napthyl, heteroaryl, bicyclic heteroaryl, phenoxy,naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio,naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl,naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl,phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclicheteroarylsulfonyl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, bicyclic heteroaryl(C₁-C₃)alkyl,phenyl(C₁-C₃)alkoxy, naphthyl(C₁-C₃)alkoxy, heteroaryl(C₁-C₃)alkoxy, andbicyclic heteroaryl(C₁-C₃)alkoxy, each optionally substituted with 1 to5 groups independently selected from: fluorine, chlorine, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonyl, (C₁-C₆)alkoxy-carbonyl, and aminocarbonyl;X and Y is each independently CH₂ or a single bond;

R² is substituted or unsubstituted (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl,(C₂-C₁₂)alkynyl, (C₁-C₁₂)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₂)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)alkylthio(C₁-C₆)alkylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, aminocarbonylamino(C₁-C₁₂)alkyl,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)-alkanoylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkyl, aminosulfonylamino(C₁-C₁₂)alkoxy,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio, wherein thesubstituted (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,(C₁-C₁₂)alkoxy, (C₁-C₁₂)alkylthio, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkoxy,(C₁-C₆)alkylthio(C₁-C₆)alkylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, aminocarbonylamino(C₁-C₁₂)alkyl,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)-alkanoylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C_(r) C₁₂)alkyl, aminosulfonylamino(C₁-C₁₂)alkoxy,aminosulfonylamino(C₁-C₁₂)alkylthio,C₁-C₆)alkanesulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio represented by R² issubstituted by at least one of:

a) one or more halogen atoms, and

b) one substitutent selected from cyano, hydroxyl, (C₁-C₃)alkoxy,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkoxy,halo(C₃-C₆)cycloalkyl, and halo(C₃-C₆)cycloalkoxy, and

wherein the thio-moiety of said unsubstituted or substituted(C₁-C₁₂)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkoxy,(C₁-C₆)alkylthio(C₁-C₆)alkylthio, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio, is optionallyreplaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or a sulfonyl (sulfone,i.e., —S(O)₂—) moiety, and

wherein the carbonyl moiety of said unsubstituted or substitutedaminocarbonylamino(C₁-C₁₂)alkyl, aminocarbonylamino(C₁-C₁₂)alkoxy,aminocarbonylamino(C₁-C₁₂)alkylthio, (C₁-C₆)-alkanoylamino(C₁-C₆)alkyl,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy, (C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio is optionally replacedby a thiocarbonyl moiety,

R³ is 1) H, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxyl,hydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)alkylamino-carbonylamino,di(C₁-C₆)alkylaminocarbonylamino, (C₁-C₆)alkanesulfonylamino,(C₁-C₆)alkylaminosulfonylamino, or di(C₁-C₆)alkylaminosulfonyl-amino, or2) phenylamino or heteroarylamino in which each phenylamino andheteroarylamino, group is optionally substituted with 1 to 5 groupsindependently selected from:fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)-cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)-cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, amino-carbonyl,(C₁-C₆)alkylaminocarbonyl, and di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl;

provided that when R³ is hydroxyl, halogen or optionally substitutedphenylamino or heteroarylamino, then R² is not a substituted orunsubstituted (C₁-C₁₂)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₂)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)-alkylthio(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonyl-amino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy, (C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkoxy, aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio,

provided further that when R³ is hydroxyl, halogen or optionallysubstituted phenylamino or heteroarylamino, then R² is not aunsubstituted or substituted (C₁-C₁₂)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio anddi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio wherein the thiomoietymoiety is replaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or a sulfonyl(sulfone, i.e., —S(O)₂—)moiety, and

provided further that when R³ is hydroxyl, halogen or optionallysubstituted phenylamino or heteroarylamino, then R² is not aunsubstituted or substituted aminocarbonylamino(C₁-C₁₂)alkoxy,aminocarbonylamino(C₁-C₁₂)alkylthio, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio, wherein the carbonylmoiety is replaced by a thiocarbonyl moiety,

A is a saturated or unsaturated 4-, 5-, 6-, or 7-membered ring which isoptionally bridged by (CH₂)_(m) via bonds to two members of said ring,wherein said ring is composed of carbon atoms, and 0-2 hetero atomsselected from 0, 1, or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1sulfur atoms, said ring atoms being substituted with the appropriatenumber of hydrogen atoms, said ring being optionally substituted with upto four independently selected halogen atoms, (C₁-C₆)alkyl groups,halo(C₁-C₆)alkyl groups or oxo groups, and wherein m is 1 to 3;Q and Y are attached to carbon or nitrogen atoms in ring A in a 1,2 or1,3 or 1,4 relationship;Q is a divalent radical selected from

R⁴ is H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl; (C₁-C₃)alkoxy(C₁-C₃)alkyl, orcyano(C₁-C₆)alkyl;L is 1) a linear (C₂-C₄)alkyl chain when G is OH, OR⁹, NH₂, NHR⁹,NR⁹R¹⁰, NHC(═NH)NH₂, or NHC(═NH)NHR⁹, or 2) a linear (C₁-C₃)alkyl chainwhen G is C(═NH)NH₂ or C(═NH)NHR⁹;L is optionally substituted by 1-4 groups independently selected fromR⁵, R⁶, R⁷, and R⁸;one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6-, or7-membered saturated ring composed of carbon atoms, and 0-2 hetero atomsselected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1sulfur atoms; said saturated ring being optionally substituted with upto four groups selected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,halo(C₄-C₇)cycloalkylalkyl, and oxo;R⁵, R⁶, R⁷, and R⁸ is each independently selected from 1) (C₁-C₁₂)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₂-C₁₂)alkenyl,(C₆-C₈)cycloalkyl(C₁-C₃)alkenyl, (C₂-C₁₂)alkynyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkynyl, (C₄-C₁₂)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₄)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, saturated heterocyclyl, and saturatedheterocyclyl(C₁-C₃)alkyl wherein (a) hydrogen atoms in these groups areoptionally substituted by 1 to 6 groups independently selected fromhalogen, cyano, hydroxyl, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkyl,halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkoxy andwherein (b) divalent sulfur atoms are optionally oxidized to sulfoxideor sulfone; or 2) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl,naphthyl(C₁-C₃)alkyl, and heteroaryl(C₁-C₃)alkyl, each optionallysubstituted with 1 to 3 groups independently selected from:fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cyclo-alkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl, phenyl, napthyl, heteroaryl,bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclicheteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclicheteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl,bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl,heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl,napthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclicheteroaryl(C₁-C₃)alkyl, wherein the aromatic and heteroaromatic groupsare optionally substituted with 1 to 3 groups independently selectedfrom fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)-alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;G is OH, OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, C(═NH)NH₂, C(═NH)NHR⁹, NHC(═NH)NH₂, orNHC(═NH)NHR⁹;R⁹ is a) (C₁-C₁₂)alkyl, (C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl,halo(C₄-C₁₂)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl,halo(C₂-C₁₂)alkenyl, halo(C₅-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl,(C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl,halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₆)alkane-sulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylamino-carbonyl(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, saturatedheterocyclyl, or saturated heterocyclyl(C₁-C₆)alkyl or b) phenyl,naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl, each optionally substituted by 1 to 3 groupsindependently selected from:1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; or 2) phenyl, napthyl,heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy,bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio,bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl,heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl,naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl,phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, andbicyclic heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3groups independently selected from fluorine, chlorine, cyano,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy,(C₁-C₃)alkanesulfonyl, and (C₁-C₃)-alkoxycarbonyl; orb) R⁹ is a saturated divalent radical composed of carbon atoms, and 0, 1or 2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygenatoms, and 0 or 1 sulfur atoms that is attached to any core carbon atomon L to form a saturated 3-, 4-, 5-, 6-, or 7-membered L-G ring; saidL-G ring being optionally substituted with 1 to 4 groups selected fromhalogen, fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl,hydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl and oxo;R¹⁹ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;provided that when R² is (C₁-C₁₂)alkyl and R³ is OH, only a singlesubstituent R⁵ is allowed on L;and the enantiomers, diastereomers, and salts thereof.

A second embodiment of the invention is a compound of Formula I wherein:

R¹ is a) (C₁-C₉)alkyl, (C₃-C₇)cycloalkyl, (C₄-C₉)cycloalkylalkyl,halo(C₁-C₉)alkyl, halo(C₃-C₇)cycloalkyl, halo(C₄-C₉)cycloalkylalkyl,saturated heterocyclyl optionally substituted with 1 to 3 groupsindependently selected from fluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,and oxo;or b) phenyl, napthyl, heteroaryl, or bicyclic heteroaryl eachoptionally substituted with 1 to 3 groups independently selected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₂)alkyl(C₃-C₆)cycloalkyl,di(C₁-C₂)alkyl(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkenyl, (C₅-C₈)cycloalkylalkenyl,(C₃-C₆)cycloalkyl-ethynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)-cycloalkyl,halo(C₄-C₇)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₇)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₇)cycloalkylalkyl, halo(C₅-C₇)-cycloalkylethynyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,(C₁-C₂)alkyl(C₃-C₇)cycloalkoxy, (C₁-C₂)alkyl(C₄-C₇)cycloalkylalkoxy,di(C₁-C₂)-alkyl(C₃-C₇)cycloalkoxy,di(C₁-C₂)alkyl(C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)-cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)-alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, piperidino, and pyrrolidino; or2) phenyl, napthyl, heteroaryl, bicyclic heteroaryl, phenoxy,naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio,naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl,naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl,phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclicheteroarylsulfonyl, phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, or, bicyclic heteroaryl(C₁-C₃)alkyl,phenyl(C₁-C₃)alkoxy, naphthyl(C₁-C₃)alkoxy, heteroaryl(C₁-C₃)alkoxy, andbicyclic heteroaryl(C₁-C₃)alkoxy, each optionally substituted with 1 to3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl,(C₁-C₃)-alkoxycarbonyl, and aminocarbonyl;X and Y is each a single bond;

R² is a substituted or unsubstituted (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₁-C₁₀)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, (C₁-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl, aminocarbonylamino(C₁-C₁₀)alkyl,aminocarbonylamino(C₁-C₁₀)alkoxy, aminocarbonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkylthio, aminosulfonylamino(C₁-C₁₀)alkyl,aminosulfonylamino(C₁-C₁₀)alkoxy, aminosulfonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkane-sulfonylamino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio, wherein thesubstituted (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,(C₁-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl, aminocarbonylamino(C₁-C₁₀)alkyl,aminocarbonylamino(C₁-C₁₀)alkoxy, aminocarbonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₁-C₁₀)alkyl, aminosulfonylamino(C₁-C₁₀)alkoxy,aminosulfonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkane-sulfonylamino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio represented by R² issubstituted by at least one of: (a) 1 to 5 fluorine atoms and (b) by onegroup selected from cyano, hydroxyl, (C₁-C₃)alkoxy, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkoxy, halo(C₁-C₃)alkoxy, halo(C₃-C₄)cycloalkyl, andhalo(C₃-C₄)cycloalkoxy, and

wherein the thio-moiety of the unsubstituted or substituted(C₁-C₁₀)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio, aminocarbonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio ordi(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio represented by R² isoptionally replaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or asulfonyl (sulfone, i.e., —S(O)₂—) moiety, and

wherein the carbonyl moiety of the unsubstituted or substitutedaminocarbonylamino(C₁-C₁₀)alkyl, aminocarbonylamino(C₁-C₁₀)alkoxy,aminocarbonylamino(C₁-C₁₀)alkylthio, (C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy, (C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy anddi(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio represented by R² isoptionally replaced with a thiocarbonyl,

R³ is H, halogen, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, hydroxyl,hydroxy(C₁-C₃)alkyl, hydroxy(C₁-C₃)alkoxy, (C₁-C₄)alkanoylamino,(C₁-C₃)alkoxycarbonylamino, (C₁-C₃)alkylamino-carbonylamino,di(C₁-C₃)alkylaminocarbonylamino, (C₁-C₃)alkanesulfonylamino,(C₁-C₃)alkylaminosulfonylamino di(C₁-C₃)alkylaminosulfonylamino,phenylamino, or heteroarylamino in which each phenylamino andheteroarylamino group is optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;

provided that when R³ is hydroxyl, halogen, or optionally substitutedphenylamino or heteroarylamino, then R² is not a substituted orunsubstituted (C₁-C₁₀)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, (C₁-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,aminocarbonylamino(C₁-C₁₀)alkoxy, aminocarbonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy, (C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₁-C₁₀)alkoxy, aminosulfonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkane-sulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkoxy ordi(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,

provided further that when R³ is hydroxyl, halogen, or optionallysubstituted phenylamino or heteroarylamino, then R² is not aunsubstituted or substituted (C₁-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,aminocarbonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₁-C₁₀)alkylthio,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio wherein the thiomoiety is replaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or a sulfonyl(sulfone, i.e., —S(O)₂—) moiety, and

provided further that when R³ is hydroxyl, halogen, or optionallysubstituted phenylamino or heteroarylamino, then R² is not aunsubstituted or substituted aminocarbonylamino(C₁-C₁₀)alkoxy,aminocarbonylamino(C₁-C₁₀)alkylthio, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy anddi(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkylthio, wherein the carbonylmoiety is replaced with a thiocarbonyl moiety

A is a saturated or unsaturated 4-, 5-, 6- or 7-membered ring whereinsaid ring is composed of carbon atoms, and 0-2 hetero atoms selectedfrom 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfuratoms, said ring atoms being substituted with the appropriate number ofhydrogen atoms; said ring being optionally substituted with up to fourindependently selected halogen atoms, (C₁-C₆)alkyl groups,halo(C₁-C₆)alkyl groups, and oxo groups;and Y are attached to carbon or nitrogen atoms in ring A in a 1,3relationship;Q is a divalent radical selected from:

R⁴ is H, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl; (C₁-C₂)alkoxy(C₁-C₂)alkyl, orcyano(C₁-C₃)alkyl;L is 1) a linear (C₂-C₃)alkyl chain when G is OH, OR⁹, NH₂, NHR⁹,NHC(═NH)NH₂, or NHC(═NH)NHR⁹ or 2) a linear (C₁-C₂)alkyl chain when G isC(═NH)NH₂ or C(═NH)NHR⁹;L is optionally substituted by 1-4 groups independently selected fromR⁵, R⁶, R⁷, and R⁸;one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6- or7-membered saturated ring composed of carbon atoms, and 0-2 heteroatomsselected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1sulfur atoms; said saturated ring being optionally substituted with upto four groups selected from fluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,halo(C₄-C₇)cycloalkylalkyl, and oxo;R⁵, R⁶, R⁷, and R⁸ is each independently 1) (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₃)alkyl, (C₂-C₁₀)alkenyl,(C₅-C₇)cycloalkyl(C₁-C₃)alkenyl, (C₂-C₁₀)alkynyl,(C₃-C₇)cycloalkyl(C₁-C₃)alkynyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₃-C₇)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₃-C₇)cycloalkylthio(C₁-C₃)alkyl, saturated heterocyclyl, or saturatedheterocyclyl(C₁-C₃)alkyl wherein (a) hydrogen atoms in these groups areoptionally substituted by 1 to 6 groups independently selected fromfluorine, cyano, hydroxyl, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,halo(C₁-C₃)alkyl, halo(C₁-C₃)alkoxy and wherein (b) divalent sulfuratoms are optionally oxidized to sulfoxide or sulfone; or 2) phenyl,naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;G is OH, OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, C(═NH)NH₂, C(═NH)NHR⁹, NHC(═NH)NH₂, orNHC(═NH)NHR⁹;R⁹ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkenyl, (C₅-C₁₀)cycloalkylalkenyl,halo(C₂-C₁₀)alkenyl, halo(C₅-C₁₀)cycloalkylalkenyl, (C₂-C₁₀)alkynyl,(C₅-C₁₀)cycloalkylalkynyl, halo(C₂-C₁₀)alkynyl,halo(C₅-C₁₀)cycloalkylalkynyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl, aminocarbonyl(C₁-C₅)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl cyano(C₁-C₅)alkyl, saturatedheterocyclyl, saturated heterocyclyl(C₁-C₃)alkyl or b) phenyl, naphthyl,heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl each optionally substituted by 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl; orb) R⁹ is a saturated divalent radical composed of carbon atoms, 0 or 1nitrogen atom, 0 or 1 oxygen atoms, and 0, or 1 sulfur atoms that isattached to any core carbon atom on the chain L to form a saturated 3-,4-, 5-, 6- or 7-membered ring; said ring being optionally substitutedwith 1-4 groups selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl,hydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl and oxo;R¹⁰ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;provided that when R² is (C₁-C₁₀)alkyl and R³ is OH, only a singlesubstituent R⁵ is allowed on L;and the enantiomers, diastereomers and salts thereof.

A third embodiment of the invention is a compound of Formula I, whereinR¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl optionally substituted with 1 to 3 groups independentlyselected from:

1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₆)cycloalkenyl, (C₅-C₈)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkylethynyl, halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl,halo(C₄-C₇)-cycloalkylalkyl, halo(C₂-C₆)alkenyl, halo(C₃-C₆)alkynyl,halo(C₃-C₆)cycloalkylethynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy,(C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy,halo(C₄-C₇)cycloalkylalkoxy, (C₃-C₆)alkenyloxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, halo(C₁-C₃)alkoxy, and aminocarbonyl;X and Y is each a single bond;R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl, fluoro(C₁-C₈)alkyl,fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₄-C₈)cycloalkylalkoxy, fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl,(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₈)alkoxy,(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,R³ is H, halogen, OH, (C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy;provided that when R³ is OH or halogen, then R² is not (C₁-C₈)alkoxy,(C₄-C₈)cycloalkylalkoxy, fluoro(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₈)alkoxy,(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoyl-amino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoyl-amino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkoxy, (C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,A is a saturated 5-, 6-, or 7-membered ring wherein said ring iscomposed of carbon atoms and 0-2 heteroatoms selected from 0 or 1nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms; said ringatoms being substituted with the appropriate number of hydrogen atoms;said ring being optionally substituted with up to four independentlyselected fluorine atoms, (C₁-C₃)alkyl groups, halo(C₁-C₃)alkyl groups,or oxo groups;the substituents Q and Y are attached in a 1,3 relationship;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;L is C₂ alkyl in which one hydrogen atom is optionally replaced with R⁵and a second hydrogen atom is optionally replaced with R⁶;R⁵ is a) (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl(C₁-C₂)alkyl,fluoro(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,fluoro(C₃-C₇)cycloalkyl(C₁-C₂)alkyl, hydroxylatedfluoro(C₃-C₇)cycloalkyl(C₁-C₂)alkyl, hydroxylated(C₃-C₇)cycloalkyl(C₁-C₂)alkyl,(C₁-C₂)alkyl(C₃-C₇)cycloalkyl(C₁-C₂)alkyl,di(C₁-C₂)alkyl(C₃-C₇)cycloalkyl(C₁-C₂)alkyl, hydroxylated(C₁-C₂)alkyl(C₃-C₇)cycloalkyl(C₁-C₂)alkyl, hydroxylateddi(C₁-C₂)alkyl(C₃-C₇)cycloalkyl(C₁-C₂)alkyl,(C₄-C₁₀)bicycloalkyl(C₁-C₂)alkyl, (C₈-C₁₂)tricycloalkyl(C₁-C₂)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₃-C₇)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;R⁶ is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₃)alkoxy(C₁-C₃)alkyl;R⁷ and R⁸ are absent;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, aminocarbonyl(C₁-C₅)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, ordi(C₁-C₆)alkyl-aminocarbonyl(C₁-C₆)alkyl; or b) phenyl(C₁-C₂)alkyloptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;or c) is attached to L and is —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— optionallysubstituted with 1 or 2 groups independently selected from fluorine,(C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, andhydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl;R¹³ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl;provided that when R² is (C₁-C₈)alkyl and R³ is OH, only a singlesubstituent R⁵ is allowed on L;and the enantiomers, diastereomers and salts thereof.

A fourth embodiment of the invention is a compound of Formula I, whereinR¹ is a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl,3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl,4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl,7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyloptionally substituted with 1 to 3 substituents independently selectedfrom:

fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, t-butyl,isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1-yl,cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio,allyloxy, cyclopropylmethoxy, 2-(cyclopropyl)ethoxy, cyclopentyloxy,cyclopentylmethoxy, benzyloxy, hydroxyl, aminocarbonyl, methoxycarbonyl,phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenylphenoxy, benzyloxy and heteroaryloxy groups are optionally substitutedwith 1 to 3 substituents independently selected from fluorine, chlorine,cyano, methyl, ethyl, trifluoromethyl, and aminocarbonyl;X and Y is each a single bond;R² is methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy,3,3,3-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl,4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl,4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy, 3-methoxypropyl,3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 2-(ethoxy)ethoxy,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy,2-cyclopropylethoxy, (2-(methoxy)ethoxy)methyl, 3-(acetylamino)propyl,3-(propionylamino)propyl, 3-(butanoylamino)propyl,3-((2-methoxypropionyl)amino)propyl,3-(cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl,3-(methylaminocarbonylamino)propyl,3-(dimethylaminocarbonylamino)propyl, 2-(acetylamino)ethoxy,2-(propionylamino)ethoxy, methoxymethylcarbonylaminomethyl,3-(aminosulfonylamino)propyl or 3-(methanesulfonylamino)propyl;R³ is H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino,propionylamino, (2-methylpropionyl)amino, or butanoylamino, providedthat when R³ is F or OH, R² is not 2-(ethoxy)ethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, 2-cyclopropylethoxy,2-(acetylamino)ethoxy or 2-(propionylamino)ethoxy;A is 2,4-disubstituted morpholine with R¹XCR²R³Y attached at the2-position and Q attached at the 4-position, 1,3-disubstitutedpiperidine with R¹XCR²R³Y attached at the 3-position and Q attached atthe 1-position, 1,3-disubstituted-3-methylpiperidine with R¹XCR²R³Yattached at the 3-position and Q attached at the 1-position,1,3-disubstituted benzene, or 1,3-disubstituted cyclohexane;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or methyl;L is a C₂ alkyl chain in which one hydrogen atom is optionally replacedwith a group selected from R⁵;R⁵ is methyl, isobutyl, t-butylmethyl, 2,2,2-trifluoroethyl,2-(trifluoromethyl)propyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-(cyclohexyl)ethyl, (3-noradamantyl)methyl,(3,3-difluorocyclobutyl)methyl, (3,4-difluorocyclopentyl)methyl,4,4-difluorocyclohexylmethyl, (4-methylcyclohexyl)methyl,tert-butoxymethyl, (2-tetrahydrofuranyl)methyl,(2-tetrahydropyranyl)methyl, (4-tetrahydropyranyl)methyl,(3-methoxycyclobutyl)methyl, (4-methoxycyclohexyl)methyl, benzyl,phenethyl, (1-fluorocyclohexyl)methyl, (4-fluorocyclohexyl)methyl,1-hydroxy-2-methylpropyl, (cyclopentyl)(hydroxy)methyl,(cyclohexyl)(hydroxy)methyl, (4-fluorocyclohexyl)(hydroxy)methyl,(cycloheptyl)(hydroxy)methyl, (1-hydroxycyclohexyl)methyl,(4-hydroxycyclohexyl)methyl, (4-hydroxy-4-methylcyclohexyl)methyl,(3-noradamantyl)(hydroxy)methyl, 2-methoxy-2-methylpropyl, or2,2-dimethyl-3-methoxypropyl;R⁶ is absent or is methyl or hydroxymethyl;R⁷ and R⁸ are absent;

G is NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl,aminocarbonylmethyl, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₂CH(c-hex)-, or—(CH₂)₂CH(OCH(C₂H₅)₂)—;R¹⁰ is methyl;provided that when R² is methyl, ethyl, propyl, butyl, pentyl or hexyland R³ is OH, R⁶ is absent;and the enantiomers, diastereomers, and salts thereof.

A fifth embodiment of the invention is a compound of Formula II:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, halo(C₁-C₁₀)alkylthio,hydroxy(C₁-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)-alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)-cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylamino-carbonylamino(C₁-C₅)alkoxy, di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,R³ is H, F, OH, (C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;R⁶ is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₃)alkoxy(C₁-C₃)alkyl;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁵ and R⁹ together are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—,optionally substituted with 1 or 2 groups independently selected fromfluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, andhydroxylated(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected;R¹³ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andprovided that when R² is (C₁-C₁₀)alkyl and R³ is OH, R⁶ is not(C₁-C₃)alkoxy(C₁-C₃)alkyl:the enantiomers, diastereomers and salts thereof.

A sixth embodiment of the invention is a compound of Formula IIa withthe stereochemical configuration shown:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-alkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl,benzyloxy, and heteroaryloxy, each optionally substituted with 1 to 3groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl, fluoro(C₁-C₈)alkyl,fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy, (C₄-C₈)cycloalkylalkoxy,fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₄)cycloalkoxy(C₁-C₅)alkyl,fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl, fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₁-C₈)alkoxy, (C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy, fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,R³ is H, F, OH, (C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C_(r) C₅)alkylthio,

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₂)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₂)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁶ is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₃)alkoxy(C₁-C₃)alkyl;R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁵ and R⁹ together are —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— and form a 4-,5-, 6-, or 7-membered ring with the atoms through which they areconnected that is optionally substituted with 1 or 2 groupsindependently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, andhydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl;R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andprovided that when R² is (C₁-C₁₀)alkyl and R³ is OH, R⁶ is not(C₁-C₃)alkoxy(C₁-C₃)alkyl:the salts thereof.

A seventh embodiment of the invention is a compound of Formula IIa,wherein:

R¹ is a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl,3-thienyl, 2-pyridyl, 2-imidazolyl, or 2-thiazolyl, optionallysubstituted with 1 to 3 substituents independently selected from:fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl,trifluoromethyl, allyl, cyclopropylethynyl, methoxy, trifluoromethoxy,neopentyloxy, methylthio, allyloxy, cyclopropylmethoxy,2-(cyclopropyl)ethoxy, cyclopentyloxy, cyclopentylmethoxy, benzyloxy,hydroxyl, aminocarbonyl, methoxycarbonyl, phenyl, phenoxy, benzyloxy,and 3-pyridyloxy, wherein the phenyl and phenoxy, benzyloxy andpyridyloxy groups are optionally substituted with 1 to 3 substituentsindependently selected from fluorine, chlorine, cyano, methyl, ethyl,and trifluoromethyl;or c) 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl,2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl,7-indazolyl, or 8-quinolinyl, optionally substituted with 1 to 3substituents independently selected from fluorine, methyl, isobutyl, andt-butyl;R² is hydrogen, methyl, ethyl, propyl, butyl, hexyl, 5-pentenyl,3,3,3-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl,4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl,4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy, 3-ethoxypropyl,4-methoxybutyl, 4-ethoxybutyl, 2-(ethoxy)-ethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, 2-cyclopropylethoxy,(2-(methoxy)ethoxy)methyl, 3-(acetylamino)propyl,3-(propionylamino)propyl, 3-(butanoylamino)propyl,3-((2-methoxypropionyl)amino)propyl,3-(cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl,3-(methylaminocarbonylamino)propyl,3-(dimethylaminocarbonylamino)propyl, methoxymethylcarbonylaminomethyl,or 3-(aminosulfonylamino)propylR³ is H, F, OH, methoxy, 3-hydroxypropoxy, acetylamino, propionylamino,(2-methylpropionyl)amino, or butanoylamino;provided that when R³ is F or OH, R² is not 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, or 2-cyclopropylethoxy;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or methyl;R⁵ is methyl, isobutyl, t-butylmethyl, 2,2,2-trifluoroethyl,2-(trifluoromethyl)propyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-(cyclohexyl)ethyl, (3-noradamantyl)methyl,(3,3-difluorocyclobutyl)methyl, (3,4-difluorocyclopentyl)methyl,(4,4-difluorocyclohexyl)methyl, (4-methylcyclohexyl)methyl,tert-butoxymethyl, (2-tetrahydrofuranyl)methyl,(2-tetrahydropyranyl)methyl, (4-tetrahydro-pyranyl)methyl,(3-methoxycyclobutyl)methyl, (4-methoxycyclohexyl)methyl, benzyl,phenethyl, (1-fluorocyclohexyl)methyl, (4-fluorocyclohexyl)methyl,1-hydroxy-2-methylpropyl, (cyclopentyl)(hydroxy)methyl,(cyclohexyl)(hydroxy)methyl, (4-fluorocyclohexyl)(hydroxy)methyl,(cycloheptyl)(hydroxy)methyl, (1-hydroxycyclohexyl)methyl,(4-hydroxycyclohexyl)methyl, (3-noradamantyl)(hydroxy)methyl, or2-methoxy-2-methylpropyl;R⁶ is absent or is methyl or hydroxymethyl;

G is NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is methyl, ethyl, propyl, butyl, isobutyl, pentyl or isopentyl,2,2,2-trifluoroethyl, 2-methoxyethyl, or aminocarbonylmethyl; or R⁹together with R⁵ is —(CH₂)₃—, —(CH₂)₄—(CH₂)₂CH(c-hex)-, or—(CH₂)₂CH(OCH(C₂H₅)₂)—;R¹⁰ is methyl;and the salts thereof.

An eighth embodiment of the invention is a compound of Formula II:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, halo(C₁-C₁₀)alkylthio,hydroxy(C₁-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)-alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)-cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,R³ is H, F, OH, (C₁-C₄)alkanoylamino, (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₃)alkoxy(C₁-C₃)alkyl;R⁶ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl, each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁶ and R⁹ together are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—,optionally substituted with 1 or 2 groups independently selected fromfluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, andhydroxylated(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected;R¹⁶ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andprovided that when R² is (C₁-C₁₀)alkyl and R³ is OH, R⁶ is not(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl;the enantiomers, diastereomers, and salts thereof.

A ninth embodiment of the invention is a compound of Formula IIb withthe stereochemical configuration shown:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl, optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-alkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl,benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl, fluoro(C₁-C₈)alkyl,fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy, (C₄-C₈)cycloalkylalkoxy,fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₄)cycloalkoxy(C₁-C₅)alkyl,fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl, fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₁-C₈)alkoxy, (C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy, fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C_(r C)₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,R³ is H, F, OH, (C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is absent or is (C₁-C₃)alkyl or hydroxy(C₁-C₃)alkyl;R⁶ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,hydroxy(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₄-C₁₀)cycloalkylalkyl, (C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₂)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₂)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl, each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁶ and R⁹ together are —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— and form a 4-,5-, 6-, or 7-membered ring with the atoms through which they areconnected that is optionally substituted with 1 or 2 groupsindependently selected from fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, andhydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl;R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andthe salts thereof.

A tenth embodiment of the invention is a compound of Formula II:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, halo(C₁-C₁₀)alkylthio,hydroxy(C₁-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)-alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)-cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, di(C₁-C₅)alkylaminocarbonylamino(C_(r) C₅)alkylthio,R³ is H, F, OH, (C₁-C₄)alkanoylamino, (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C_(r) C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;

R⁶ is H G is NHR⁹;

R⁵ and R⁹ together are —(CH₂)₃—, optionally substituted with 1 or 2groups independently selected from the group consisting of fluorine,(C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, andhydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl;the enantiomers, diastereomers, and salts thereof.

An eleventh embodiment of the invention is a compound of Formula IIcwith the stereochemical configuration shown:

wherein

Z is CH₂ or O;

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl, optionally substituted with 1 to 3 groups independentlyselected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-alkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl,benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;R² is (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cyclo-alkylalkyl, (C₁-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, halo(C₁-C₁₀)alkylthio,hydroxy(C₁-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylamino-carbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,R³ is H, F, OH, (C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy;provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₅)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkyl-aminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R¹¹ is fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl,hydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl;and the salts thereof.

Another embodiment of the invention provides compounds of Formula Ia

whereinR¹ is a) (C₁-C₁₂)alkyl, (C₃-C₇)cycloalkyl, (C₄-C₁₂)cycloalkylalkyl,halo(C₁-C₁₂)alkyl, halo(C₃-C₇)-cycloalkyl, halo(C₄-C₁₂)cycloalkylalkyl,saturated heterocyclyl optionally substituted with 1 to 5 groupsindependently selected from: fluorine, (C₁-C₆)alkyl, halo(C₁-C₆)alkyland oxo;or b) phenyl, napthyl, heteroaryl or bicyclic heteroaryl each optionallysubstituted with 1 to 5 groups independently selected from:1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)cyclo-alkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₅-C₆)cycloalkenyl, halo(C₆-C₇)cycloalkenylalkyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)-cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkyl-alkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)-cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkane-sulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylamino-carbonyl, and di(C₁-C₆)alkylaminocarbonyl; or2) phenyl, napthyl, heteroaryl, bicyclic heteroaryl, phenoxy,naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio,naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl,naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl,phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclicheteroarylsulfonyl, phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, bicyclic heteroaryl(C₁-C₃)alkyl, each optionallysubstituted with 1 to 5 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxy-carbonyl;X and Y is each independently CH₂ or a single bond;R² is (C₁-C₁₂)alkyl, (C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl,halo(C₄-C₁₂)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl,halo(C₂-C₁₂)alkenyl, halo(C₅-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl,(C₅-C₁₂)cycloalkylalkynyl, halo(C₃-C₁₂)alkynyl,halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₁₂)alkoxy, (C₄-C₁₂)cycloalkylalkoxy,halo(C₁-C₁₂)alkoxy, (C₁-C₁₂)alkylthio, halo(C₁-C₁₂)alkylthio,(C₁-C₁₂)alkanesulfinyl, halo(C₁-C₁₂)alksulfinyl, (C₁-C₁₂)alkanesulfonyl,halo(C₁-C₁₂)alksulfonyl, hydroxy(C₁-C₁₂)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₆)-alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)cycloalkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)cycloalkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)-alkoxy, halo(C₁-C₆)cycloalkoxy(C₁-C₆)alkoxy,hydroxy(C₁-C₁₂)alkylthio, (C₁-C₆)alkoxy(C₁-C₆)-alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)alkylthio(C₁-C₆)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)-alkylsulfinyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkoxy,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkylsulfinyl,(C₁-C₆)-alkoxy(C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylsulfonyl(C₁-C₆)alkoxy,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-sulfonyl,(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, cyano(C₁-C₁₂)alkyl,cyano(C₁-C₁₂)alkoxy, cyano(C₁-C₆)alkoxy(C₁-C₆)alkyl,cyano(C₁-C₆)alkoxy-(C₁-C₆)alkoxy, cyano(C₁-C₆)alkoxy(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₁₂)alkyl, aminocarbonylamino(C₁-C₁₂)alkoxy,aminocarbonylamino(C₁-C₁₂)alkylthio, (C₁-C₆)alkanoyl-amino(C₁-C₆)alkyl,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy, (C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkyl, aminosulfonylamino(C₁-C₁₂)alkoxy,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy, or(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio;R³ is H, halogen, (C₁-C₆)alkyl, hydroxyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)alkylaminocarbonylamino, di(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkanesulfonylamino, (C₁-C₆)alkylaminosulfonylamino,di(C₁-C₆)alkylaminosulfonyl-amino, or phenylamino or heteroarylamino inwhich each phenylamino and heteroarylamino group is optionallysubstituted with 1 to 5 groups independently selected from:fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)-cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)-cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, amino-carbonyl,(C₁-C₆)alkylaminocarbonyl, and di(C₁-C₆)alkylaminocarbonyl;provided that when R³ is hydroxyl, halogen or optionally substitutedphenylamino or heteroarylamino, R² is not (C₁-C₁₂)alkoxy,(C₄-C₁₂)cycloalkylalkoxy, halo(C₁-C₁₂)alkoxy, (C₁-C₁₂)alkylthio,halo(C₁-C₁₂)alkylthio, (C₁-C₁₂)alkanesulfinyl, halo(C₁-C₁₂)alksulfinyl,(C₁-C₁₂)-alkanesulfonyl, halo(C₁-C₁₂)alksulfonyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)cycloalkoxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)cycloalkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkoxy,(C₁-C₆)alkylthio(C₁-C₆)alkylthio, (C₁-C₆)alkoxy(C₁-C₆)alkylsulfinyl,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkoxy,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkylsulfinyl,(C₁-C₆)alkoxy(C₁-C₆)alkylsulfonyl, (C₁-C₆)-alkylsulfonyl(C₁-C₆)alkoxy,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkylsulfonyl, cyano(C₁-C₁₂)alkoxy,cyano(C₁-C₆)alkoxy(C₁-C₆)alkoxy, cyano(C₁-C₆)alkoxy(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₆)alkoxy, aminocarbonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)-alkanoylamino(C₁-C₆)alkylthio, aminosulfonylamino(C₁-C₆)alkoxy,aminosulfonylamino(C₁-C₆)-alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy, or(C₁-C₆)alkanesulfonylamino(C₁-C₆)-alkylthio;A is a saturated or unsaturated 4-, 5-, 6-, or 7-membered ring which isoptionally bridged by (CH₂)_(m) wherein said ring is composed of carbonatoms, and 0-2 hetero atoms selected from 0, 1 or 2 nitrogen atoms, 0 or1 oxygen atoms, and 0 or 1 sulfur atoms, said ring atoms beingsubstituted with the appropriate number of hydrogen atoms, said ringbeing optionally substituted with up to four independently selectedhalogen atoms, (C₁-C₆)alkyl groups, halo(C₁-C₆)alkyl groups or oxogroups;Q and Y are attached to carbon or nitrogen atoms in ring A in a 1,2 or1,3 or 1,4 relationship;m is 1 to 3;Q is a divalent radical selected from

R⁴ is H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl; (C₁-C₃)alkoxy(C₁-C₃)alkyl, orcyano(C₁-C₆)alkyl;L is 1) a linear (C₂-C₄)alkyl chain when G is OH, OR⁹, NH₂, NHR⁹,NR⁹R¹⁰, NHC(═NH)NH₂ or NHC(═NH)NHR⁹, or 2) a linear (C₁-C₃)alkyl chainwhen G is C(═NH)NH₂ or C(═NH)NHR⁹;L is optionally substituted by 1-4 groups independently selected fromR⁵, R⁶, R⁷, and R⁸;

one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6-, or7-membered saturated ring composed of carbon atoms, and 0-2 hetero atomsselected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1sulfur atoms; said ring being optionally substituted with up to fourgroups selected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,halo(C₄-C₇)cycloalkylalkyl, and oxo;

R⁵, R⁶, R⁷, and R⁸ is each independently selected from 1) (C₁-C₁₂)alkyl,(C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl, halo(C₄-C₁₂)cycloalkylalkyl,(C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl, halo(C₂-C₁₂)alkenyl,halo(C₅-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl,(C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl,halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkane-sulfonyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, saturated heterocyclyl, or saturatedheterocyclyl(C₁-C₆)alkyl, or 2) phenyl, naphthyl, heteroaryl,phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, or heteroaryl(C₁-C₃)alkyl,each optionally substituted with 1 to 3 groups independently selectedfrom:fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cyclo-alkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cyclo-alkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, phenyl, napthyl,heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy,bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio,bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl,heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl,naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl,phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, orbicyclic heteroaryl(C₁-C₃)alkyl, wherein the aromatic and heteroaromaticgroups are optionally substituted with 1 to 3 groups independentlyselected from fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;G is OH, OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, C(═NH)NH₂, C(═NH)NHR⁹, NHC(═NH)NH₂, orNHC(═NH)NHR⁹;R⁹ is a) (C₁-C₁₂)alkyl, (C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl,halo(C₄-C₁₂)cycloalkylalkyl, (C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl,halo(C₂-C₁₂)alkenyl, halo(C₅-C₁₂)cycloalkylalkenyl, (C₂-C₁₂)alkynyl,(C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl,halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylamino-carbonyl(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, saturatedheterocyclyl, or saturated heterocyclyl(C₁-C₆)alkyl or b) phenyl,naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl, each optionally substituted by 1 to 3 groupsindependently selected from:1) fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cyclo-alkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)-cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylamino-carbonyl and di(C₁-C₆)alkylaminocarbonyl; or 2)phenyl, napthyl, heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy,heteroaryloxy, bicyclic heteroaryloxy, phenylthio, naphthylthio,heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl,naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl,phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclicheteroarylsulfonyl, phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, and bicyclic heteroaryl(C₁-C₃)alkyl, eachoptionally substituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkane-sulfonyl, and(C₁-C₃)alkoxycarbonyl; orb) R⁹ is a saturated divalent radical composed of carbon atoms, and 0, 1or 2 hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygenatoms, and 0 or 1 sulfur atoms that is attached to any core carbon atomon the chain L to form a saturated 3-, 4-, 5-, 6-, or 7-membered ring;said ring being optionally substituted with 1-4 groups selected fromhalogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)cycloalkyl,halo(C₁-C₆)cycloalkyl, (C₁-C₆)cycloalkyl(C₁-C₂)alkyl,halo(C₁-C₆)cycloalkyl(C₁-C₂)alkyl, and oxo;R¹⁰ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;and the enantiomers, diastereomers, and salts thereof.

An embodiment of the invention is a compound of Formula Ia wherein:

R¹ is a) (C₁-C₉)alkyl, (C₃-C₇)cycloalkyl, (C₄-C₉)cycloalkylalkyl,halo(C₁-C₉)alkyl, halo(C₃-C₇)cycloalkyl, halo(C₄-C₉)cycloalkylalkyl,saturated heterocyclyl optionally substituted with 1 to 3 groupsindependently selected from fluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl andoxo;or b) phenyl, napthyl, heteroaryl, or bicyclic heteroaryl eachoptionally substituted with 1 to 3 groups independently selected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₃-C₆)cycloalkylethynyl,halo(C₁-C₃)alkyl, halo(C₃-C₆)-cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,halo(C₅-C₇)cycloalkylethynyl, (C₁-C₃)alkoxy, (C₃-C₆)cycloalkoxy,(C₄-C₇)cycloalkylalkoxy, halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkoxy,halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₃)alkylthio, (C₃-C₆)cycloalkythio,(C₄-C₇)cycloalkylalkylthio, halo(C₁-C₃)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₃)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₃)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkylalkanesulfonyl and(C₁-C₆)alkylamino; or2) phenyl, napthyl, heteroaryl, bicyclic heteroaryl, phenoxy,naphthyloxy, heteroaryloxy, bicyclic heteroaryloxy, phenylthio,naphthylthio, heteroarylthio, bicyclic heteroarylthio, phenylsulfinyl,naphthylsulfinyl, heteroarylsulfinyl, bicyclic heteroarylsulfinyl,phenylsulfonyl, naphthylsulfonyl, heteroarylsulfonyl, bicyclicheteroarylsulfonyl, phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, or, bicyclic heteroaryl(C₁-C₃)alkyl, eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;X and Y is each a single bond;R² is (C₂-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkenyl, (C₅-C₁₀)cycloalkylalkenyl,halo(C₂-C₁₀)alkenyl, halo(C₅-C₁₀)cycloalkylalkenyl, (C₂-C₁₀)alkynyl,(C₅-C₁₀)cycloalkylalkynyl, halo(C₃-C₁₀)alkynyl,halo(C₅-C₁₀)cycloalkylalkynyl, (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₂-C₁₀)alkanesulfinyl, halo(C₂-C₁₀)alksulfinyl, (C₂-C₁₀)alkanesulfonyl,halo(C₂-C₁₀)alksulfonyl, hydroxy(C₂-C₁₀)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)cycloalkoxy(C₁-C₅)alkyl,halo(C₁-C₅)-alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)-alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₁-C₅)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)-alkoxy, halo(C₁-C₅)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)-alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkylsulfinyl, (C₁-C₅)alkylsulfinyl(C₁-C₅)alkoxy,(C₁-C₅)alkylsulfinyl(C₁-C₅)-alkylsulfinyl,(C₁-C₅)alkoxy(C₁-C₅)alkylsulfonyl, (C₁-C₅)alkylsulfonyl(C₁-C₅)alkoxy,(C₁-C₅)alkylsulfonyl(C₁-C₅)alkyl-sulfonyl,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl, cyano(C₂-C₁₀)alkyl,cyano(C₂-C₁₀)alkoxy, cyano(C₁-C₅)alkoxy(C₁-C₅)alkyl,cyano(C₁-C₅)alkoxy-(C₁-C₅)alkoxy, cyano(C₁-C₅)alkoxy(C₁-C₅)alkylthio,aminocarbonylamino(C₂-C₁₀)alkyl, aminocarbonylamino(C₂-C₁₀)alkoxy,aminocarbonyl-amino(C₂-C₁₀)alkylthio, (C₁-C₅)alkanoyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy, (C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₂-C₁₀)alkyl, aminosulfonyl-amino(C₂-C₁₀)alkoxy,aminosulfonylamino(C₂-C₁₀)alkylthio,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy, or(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkylthio.R³ is H, halogen, (C₁-C₃)alkyl, hydroxyl, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkanoylamino, (C₁-C₃)-alkoxy-carbonylamino,(C₁-C₃)alkylaminocarbonylamino, di(C₁-C₃)alkylaminocarbonylamino,(C₁-C₃)alkanesulfonylamino, (C₁-C₃)alkylaminosulfonylaminodi(C₁-C₃)alkylaminosulfonylamino, phenylamino, or heteroarylamino inwhich each phenylamino and heteroarylamino group is optionallysubstituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;provided that when R³ is hydroxyl, halogen, or optionally substitutedphenylamino or heteroarylamino, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₂-C₁₀)alkanesulfinyl, halo(C₂-C₁₀)alksulfinyl,(C₂-C₁₀)alkanesulfonyl, halo(C₂-C₁₀)-alksulfonyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₅)alkoxy,(C₁-C₅)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₅)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkylsulfinyl,(C₁-C₅)alkylsulfinyl(C₁-C₅)alkoxy,(C₁-C₅)alkylsulfinyl(C₁-C₅)alkyl-sulfinyl,(C₁-C₅)alkoxy(C₁-C₅)alkylsulfonyl, (C₁-C₅)alkylsulfonyl(C₁-C₅)alkoxy,(C₁-C₅)alkyl-sulfonyl(C₁-C₅)alkylsulfonyl, cyano(C₂-C₁₀)alkoxy,cyano(C₁-C₅)alkoxy(C₁-C₅)alkoxy, cyano(C₁-C₅)alkoxy(C₁-C₅)alkylthio,aminocarbonylamino(C₁-C₅)alkoxy, aminocarbonylamino(C₁-C₅)alkyl-thio,(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy, (C₁-C₅)alkanoylamino(C₁-C₅)alkylthio,aminosulfonylamino(C₁-C₅)alkoxy, aminosulfonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkoxy, or(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkylthio;A is a saturated or unsaturated 4-, 5-, 6- or 7-membered ring whereinsaid ring is composed of carbon atoms, and 0-2 hetero atoms selectedfrom 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfuratoms, said ring atoms being substituted with the appropriate number ofhydrogen atoms; said ring being optionally substituted with up to fourindependently selected halogen atoms, (C₁-C₆)alkyl groups,halo(C₁-C₆)alkyl groups, and oxo groups;Q and Y are attached to carbon or nitrogen atoms in ring A in a 1,3relationship;Q is a divalent radical selected from:

R⁴ is H, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl; (C₁-C₂)alkoxy(C₁-C₂)alkyl, orcyano(C₁-C₃)alkyl;L is 1) a linear (C₂-C₃)alkyl chain when G is OH, OR⁹, NH₂, NHR⁹,NHC(═NH)NH₂, or NHC(═NH)NHR⁹ or 2) a linear (C₁-C₂)alkyl chain when G isC(═NH)NH₂ or C(═NH)NHR⁹;L is optionally substituted by 1-4 groups independently selected fromR⁵, R⁶, R⁷, and R⁸;one or more of the carbon atoms of L may be part of a 3-, 4-, 5-, 6- or7-membered saturated ring composed of carbon atoms, and 0-2 heteroatomsselected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1sulfur atoms; said ring being optionally substituted with up to fourgroups selected from fluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,halo(C₄-C₇)cycloalkylalkyl, and oxo;R⁵, R⁶, R⁷, and R⁸ is each independently a) (C₁-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl,(C₂-C₁₀)alkenyl, (C₅-C₁₀)cycloalkylalkenyl, halo(C₂-C₁₀)alkenyl,halo(C₅-C₁₀)cycloalkylalkenyl, (C₂-C₁₀)alkynyl,(C₅-C₁₀)cycloalkylalkynyl, halo(C₂-C₁₀)alkynyl,halo(C₅-C₁₀)cycloalkylalkynyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl, aminocarbonyl(C₁-C₅)alkyl,cyano(C₁-C₅)alkyl, saturated heterocyclyl, or saturatedheterocyclyl(C₁-C₃)alkyl, or b) phenyl, naphthyl, heteroaryl,phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl;G is OH, OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, C(═NH)NH₂, C(═NH)NHR⁹, NHC(═NH)NH₂, orNHC(═NH)NHR⁹;R⁹ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkenyl, (C₅-C₁₀)cycloalkylalkenyl,halo(C₂-C₁₀)alkenyl, halo(C₅-C₁₀)cycloalkylalkenyl, (C₂-C₁₀)alkynyl,(C₅-C₁₀)cycloalkylalkynyl, halo(C₂-C₁₀)alkynyl,halo(C₅-C₁₀)cycloalkylalkynyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl,halo(C₁-C₅)alkanesulfinyl(C₁-C₅)alkyl, (C_(r)C₅)alkanesulfonyl(C₁-C₅)alkyl, halo(C₁-C₅)alkanesulfonyl(C₁-C₅)alkyl,aminocarbonyl(C₁-C₅)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl cyano(C₁-C₅)alkyl, saturatedheterocyclyl, saturated heterocyclyl(C₁-C₃)alkyl or b) phenyl, naphthyl,heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl each optionally substituted by 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl; orb) R⁹ is a saturated divalent radical composed of carbon atoms, 0 or 1nitrogen atom, 0 or 1 oxygen atoms, and 0, or 1 sulfur atoms that isattached to any core carbon atom on the chain L to form a saturated 3-,4-, 5-, 6- or 7-membered ring; said ring being optionally substitutedwith 1-4 groups selected from fluorine, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,halo(C₄-C₇)cycloalkylalkyl, and oxo;R¹⁰ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;and the enantiomers, diastereomers and salts thereof.

Another embodiment of the invention is a compound of Formula Ia, wherein

R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl optionally substituted with 1to 3 groups independently selected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)-cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-lalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl and heteroarylmethyl,each optionally substituted with 1 to 3 groups independently selectedfrom:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy;X and Y is each a single bond;R² is (C₂-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,hydroxy(C₂-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₁-C₅)-alkoxy(C₁-C₅)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cyclo-alkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, (C₁-C₅)-alkylthio(C₁-C₅)alkylthio;R³ is H, halogen, or OH;provided that when R³ is OH or halogen, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio;A is a saturated 5-, 6-, or 7-membered ring wherein said ring iscomposed of carbon atoms and 0-2 heteroatoms selected from 0 or 1nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms; said ringatoms being substituted with the appropriate number of hydrogen atoms;said ring being optionally substituted with up to four independentlyselected fluorine atoms, (C₁-C₃)alkyl groups, halo(C₁-C₃)alkyl groups,or oxo groups;the substituents Q and Y are attached in a 1,3 relationship;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;L is a C₂ alkyl chain in which one hydrogen atom is optionally replacedwith a a group selected from R⁵ and a second hydrogen atom is optionallyreplaced with a group selected from R⁶;R⁵ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;R⁶ is absent or is (C₁-C₆)alkyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl;R⁷ and R⁸ are absent;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, aminocarbonyl(C₁-C₅)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, ordi(C₁-C₆)alkyl-aminocarbonyl(C₁-C₆)alkyl; or b) phenyl(C₁-C₂)alkyloptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;or c) is attached to L and is —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— optionallysubstituted with 1 or 2 groups independently selected from fluorine,(C₁-C₃)alkyl, and halo(C₁-C₃)alkyl;R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl;and the enantiomers, diastereomers and salts thereof.

Another embodiment of the invention is a compound of Formula Ia, wherein

R¹ is a) cyclohexyl; or b) phenyl optionally substituted with 1 to 3substituents independently selected from:fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl,allyl, cyclopropylethynyl, phenyl and phenoxy, wherein the phenyl andphenoxy groups are optionally substituted with 1 to 3 substituentsindependently selected from fluorine, chlorine, cyano, methyl, andtrifluoromethyl;X and Y is each a single bond;R² is butyl, hexyl, 3,3,3-trifluoropropyl, 3-(cyclopropyl)propyl,4-(cyclopropyl)butyl, 3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, or2-cyclopropylethoxy;

R³ is H, F, or OH;

provided that when R³ is F or OH, R² is not 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, or 2-cyclopropylethoxy;A is 2,4-disubstituted morpholine with R¹XCR²R³Y attached at the2-position and Q attached at the 4-position, 1,3-disubstitutedpiperidine with R¹XCR²R³Y attached at the 3-position and Q attached atthe 1-position, 1,3-disubstituted-3-methylpiperidine with R¹XCR²R³Yattached at the 3-position and Q attached at the 1-position,1,3-disubstituted benzene, or 1,3-disubstituted cyclohexane;

Q is Q1, Q4, Q9, or Q10

R⁴ is H or methyl;L is a C₂ alkyl chain in which one hydrogen atom is optionally replacedwith a a group selected from R⁵;R⁵ is methyl, isobutyl, 2-(trifluoromethyl)propyl, cyclopentylmethyl,cyclohexylmethyl, 4,4-difluorocyclohexylmethyl, tert-butoxymethyl, orbenzyl;R⁶ is absent or is methyl;R⁷ and R⁸ are absent;

G is NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl,aminocarbonylmethyl, or —(CH₂)₃—;R¹⁶ is methyl;and the enantiomers, diastereomers, and salts thereof.

Another embodiment of the invention is a compound of Formula IId:

whereinR¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl optionally substituted with 1to 3 groups independently selected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, and heteroarylmethyl, eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy;R² is (C₂-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,hydroxy(C₂-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy-(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, or (C₁-C₅)-alkylthio(C₁-C₅)alkylthio;

R³ is H, F, or OH;

provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl; or b) phenyl(C₁-C₂)alkyl, orheteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groupsindependently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁵ and R⁹ together are —CH₂—, —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₄—,optionally substituted with 1 or 2 groups independently selected fromfluorine, (C₁-C₃)alkyl and halo(C₁-C₃)alkyl, and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected;R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andsalts thereof.

Another embodiment of the invention is a compound of Formula IIe withthe stereochemical configuration shown:

whereinR¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl optionally substituted with 1to 3 groups independently selected from:1) fluorine, chlorine, bromine, cyano, nitro, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,(C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, and heteroarylmethyl, eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy;R² is (C₂-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,hydroxy(C₂-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy-(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, or (C₁-C₅)-alkylthio(C₁-C₅)alkylthio;

R³ is H, F, or OH;

provided that when R³ is OH or F, R² is not (C₂-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio,halo(C₂-C₁₀)alkylthio, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkoxy, (C₃-C₅)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₅)-cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₂-C₁₀)alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or (C₁-C₅)alkylthio(C₁-C₅)alkylthio;

Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl;R⁵ is a) (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl; or b) phenyl(C₁-C₂)alkyl, orheteroaryl(C₁-C₂)alkyl each optionally substituted with 1 to 3 groupsindependently selected fromfluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy;

G is OH, NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; orc) R⁵ and R⁹ together are —CH₂—, —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₄—,optionally substituted with 1 or 2 groups independently selected fromfluorine, (C₁-C₃)alkyl and halo(C₁-C₃)alkyl, and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected;R¹⁹ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andsalts thereof.

Another embodiment of the invention is a compound of Formula IIe,wherein:

R¹ is a) cyclohexyl; or b) phenyl optionally substituted with 1 to 3substituents independently selected from:fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl,allyl, cyclopropylethynyl, phenyl, and phenoxy, wherein the phenyl andphenoxy groups are optionally substituted with 1 to 3 substituentsindependently selected from fluorine, chlorine, cyano, methyl, andtrifluoromethyl;R² is butyl, hexyl, 3,3,3-trifluoropropyl, 3-(cyclopropyl)propyl,4-(cyclopropyl)butyl, 3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, or2-cyclopropylethoxy;

R³ is H, F, or OH;

provided that when R³ is F or OH, R² is not 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, or 2-cyclopropylethoxy;

Q is Q1, Q4, Q9, or Q10

R⁴ is H or methyl;R⁵ is methyl, isobutyl, 2-(trifluoromethyl)propyl, cyclopentylmethyl,cyclohexylmethyl, 4,4-difluorocyclohexylmethyl, tert-butoxymethyl, orbenzyl;

G is NH₂, NHR⁹, or NR⁹R¹⁰;

R⁹ is methyl, ethyl, propyl, butyl, isobutyl, pentyl or isopentyl, oraminocarbonylmethyl; or R⁹ together with R⁵ is —(CH₂)₃—;R¹⁰ is methyl;and the salts thereof.

In a preferred embodiment, the compound is represented by Formula I; R¹is as defined in the second embodiment, third or fourth embodiment andthe remainder of the variables are as defined in the first embodiment.

In another preferred embodiment, the compound is represented by FormulaI; R² is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R³ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁴ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁵ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁵ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁶ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁷ and R⁸ are as defined in the second embodiment, third or fourthembodiment and the remainder of the variables are as defined in thefirst embodiment.

In another preferred embodiment, the compound is represented by FormulaI; R⁹ is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; R¹⁰ is as defined in the second embodiment, third or fourthembodiment and the remainder of the variables are as defined in thefirst embodiment.

In another preferred embodiment, the compound is represented by FormulaI; A is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaI; X and Y are as defined in the second embodiment, third or fourthembodiment and the remainder of the variables are as defined in thefirst embodiment.

In another preferred embodiment, the compound is represented by FormulaI; Q is as defined in the second embodiment, third or fourth embodimentand the remainder of the variables are as defined in the firstembodiment.

In another preferred embodiment, the compound is represented by FormulaII; R¹ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R² is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In a preferred embodiment, the compound is represented by Formula II; R¹is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R² is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R³ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁴ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁶ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁷ and R⁸ are as defined in the fifth, sixth, seventh, eight, ninthor tenth embodiment and the remainder of the variables are as defined inthe fifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R⁹ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R¹⁰ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe fifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; A is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; X and Y are as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe fifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; Q is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R² is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R¹ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; R² is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In another preferred embodiment, the compound is represented by FormulaII; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thefifth embodiment.

In a preferred embodiment, the compound is represented by Formula IIa;R¹ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thesixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R² is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R³ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁴ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁶ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁷ and R⁸ are as defined in the fifth, sixth, seventh, eight, ninthor tenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R⁹ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R¹⁰ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; A is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thesixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; X and Y are as defined in the fifth, sixth, seventh, eight, ninthor tenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; Q is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thesixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; R² is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe sixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIa; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in thesixth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R¹ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R² is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in theninth embodiment.

In a preferred embodiment, the compound is represented by Formula IIb;R¹ is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in theninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R² is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R³ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁴ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁵ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁶ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁷ and R⁸ are as defined in the fifth, sixth, seventh, eight, ninthor tenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R⁹ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R¹⁰ is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; A is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in theninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; X and Y are as defined in the fifth, sixth, seventh, eight, ninthor tenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; Q is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in theninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; R² is as defined in the fifth, sixth, seventh, eight, ninth ortenth embodiment and the remainder of the variables are as defined inthe ninth embodiment.

In another preferred embodiment, the compound is represented by FormulaIIb; G is as defined in the fifth, sixth, seventh, eight, ninth or tenthembodiment and the remainder of the variables are as defined in theninth embodiment.

Another embodiment of the invention is each of the following compoundsand their enantiomers, diastereomers, and salts:

-   I-1    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-2    3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)benzamide-   I-3    3-((2-cyclopropylethoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-4    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-5    3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-6    3-((3-methoxypropoxy)(phenyl)methyl)-N-(2-amino-3-cyclohexylpropyl)piperidine-1-carboxamide-   I-7    N-(1-amino-3-cyclopentylpropan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-8    2-((3-methoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)morpholine-4-carboxamide-   I-9    N-(3-tert-butoxy-1-aminopropan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-10    3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-11    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide-   I-12    N-(1-amino-3-phenylpropan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-13    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxamide-   I-14    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-15    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-16    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-17    3-((3-ethoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-18    3-((4-methoxybutoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-19    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-20    3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)-N-methylpiperidine-1-carboxamide-   I-21    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-4-methoxy-1-phenylbutyl)piperidine-1-carboxamide-   I-22    3-((3-methoxypropoxy)(4-fluorophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-23    3-((3-methoxypropoxy)(2-fluorophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-24    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-cyclohexyl-5-methoxypentyl)piperidine-1-carboxamide-   I-25    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(4-cyclopropyl-1-hydroxy-1-phenylbutyl)piperidine-1-carboxamide-   I-26    3-((3-methoxypropoxy)(3-cyanophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-27    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-28    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)cyclohexanecarboxamide-   I-29    N-(1-amino-4-(trifluoromethyl)pentan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-30    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide-   I-31    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxamide-   I-32    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-33    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-34    3-((3-ethoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)-3-methylpiperidine-1-carboxamide-   I-35    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(4-ethoxy-1-hydroxy-1-phenylbutyl)piperidine-1-carboxamide-   I-36    N-(2-amino-5-methoxy-4,4-dimethylpentyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-37    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-38    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-fluoro-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-39    3-((3-methoxypropoxy)(3-fluorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-40    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-41    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-cyclohexyl-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-42    3-((3-methoxypropoxy)(2,4-difluorophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-43    3-((3-methoxypropoxy)(3,4-difluorophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-44    3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-45    3-((3-methoxypropoxy)(3-cyanophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-46    3-((3-methoxypropoxy)(2-allylphenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-47    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(propylamino)propan-2-yl)piperidine-1-carboxamide-   I-48    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-49    3-((3-propoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-50    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-51    N-(1-amino-5-methoxy-4,4-dimethylpentan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-52    N2-((Z)-1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine-   I-53    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-54    N-(2-amino-5-methoxy-4,4-dimethylpentyl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-55    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-56    3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide-   I-57    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(4,4,4-trifluoro-1-hydroxy-1-m-tolylbutyl)piperidine-1-carboxamide-   I-58    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-59    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(2-((3-methoxypropoxy)(phenyl)methyl)morpholino)cyclobut-3-ene-1,2-dione-   I-60    4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-N-(1-amino-3-cyclohexylpropan-2-yl)-1,2,5-thiadiazol-3-amine-   I-61    3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-(butylamino)-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-62    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(isobutylamino)propan-2-yl)piperidine-1-carboxamide-   I-63    N-(3-cyclohexyl-1-(dimethylamino)propan-2-yl)-3-(5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-64    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-65    3-((3-ethoxypropoxy)(3,4-difluorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-66    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-67    N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-68    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-69    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-(1-hydroxy-1-phenylheptyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-70    3-(3-amino-1-cyclohexylbutan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-71    3-(3-cyclohexyl-1-(methylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-72    3-(1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-73    3-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-4-(N-(1-amino-3-cyclohexylpropan-2-yl)-N-methylamino)cyclobut-3-ene-1,2-dione-   I-74    3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-75    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(4-fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-76    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-77    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(isopentylamino)propan-2-yl)piperidine-1-carboxamide-   I-78    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(pentylamino)propan-2-yl)piperidine-1-carboxamide-   I-79    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-1-(3-isopropylphenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-80    3-(1-(3-chlorophenyl)-4,4,4-trifluoro-1-hydroxybutyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-81    3-(1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-82    3-(1-(3-chlorophenyl)-5-cyclopropyl-1-hydroxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-83    3-((3-methoxypropoxy)(2-phenylphenyl)methyl)-N-(2-amino-3-cyclohexylpropyl)piperidine-1-carboxamide-   I-84    3-((3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-85    3-(3-cyclohexyl-1-(ethylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-86    3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-87    N-(1-amino-5-methoxy-4,4-dimethylpentan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-88    N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-89    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(2,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-90    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(3,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-91    N-(1-(carbamoylmethylamino)-3-cyclohexylpropan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-92    3-(3-cyclohexyl-1-(propylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-93    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-94    3-(3-cyclohexyl-1-(isobutylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-95    3-(3-(butylamino)-1-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-96    3-(1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-97    3-(1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-98    3-(3-cyclohexyl-1-(methylamino)propan-2-ylamino)-4-(3-((3-ethoxypropoxy)(3,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-99    3-(1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-100    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-101    3-(1-cyclohexyl-3-(pentylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-102    3-(1-cyclohexyl-3-(isopentylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione-   I-103    3-(1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-104    3-(1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-105    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((pent-4-enyloxy)(phenyl)methyl)benzamide-   I-106    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)benzamide-   I-107    3-((2-ethoxyethoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide-   I-108    3-(1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-109    3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-110    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-(thiophen-2-yl)pentyl)piperidine-1-carboxamide-   I-111    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxamide-   I-112    3-((2-(acetylamino)ethoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide-   I-113    3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-114    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)benzamide-   I-115    3-((3-ethoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide-   I-116    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-117    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-118    3-(1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-119    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(pyridin-2-yl)pentyl)piperidine-1-carboxamide-   I-120    3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-121    3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-122    3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carbothioamide-   I-123    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-124    3-(1-hydroxy-5-methoxy-1-(2-(neopentyloxy)phenyl)pentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-125    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(1-methyl-1H-imidazol-2-yl)pentyl)piperidine-1-carboxamide-   I-126    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(thiophen-2-yl)pentyl)piperidine-1-carboxamide-   I-127    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(thiophen-3-yl)pentyl)piperidine-1-carboxamide-   I-128    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-m-tolylpentyl)benzamide-   I-129    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-O—    tolylpentyl)benzamide-   I-130    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(thiazol-2-yl)pentyl)piperidine-1-carboxamide-   I-131    3-(1-(2-(3-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-132    3-(1-(2-(4-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-133    3-(1-(2-(2-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-134    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-135    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-136    3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-aminoethyl)-N-methylpiperidine-1-carboxamide-   I-137    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)benzamide-   I-138    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(4-fluorophenyl)-1-hydroxy-5-methoxypentyl)benzamide-   I-139    3-(1-hydroxy-5-methoxy-1-(quinolin-8-yl)pentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-140    3-(1-(2-(2-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-141    3-(1-(2-phenyl-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-142    3-(1-(2-(3-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-143    3-((S)-1-(2-(4-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-144    3-(1-hydroxy-5-methoxy-1-(2-methylbenzofuran-7-yl)pentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-145    3-(1-hydroxy-1-(2-isobutylbenzofuran-7-yl)-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-146    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)-3-methylpiperidine-1-carboxamide-   I-147    3-(1-(2-(cyclopentylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-148    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-fluoro-5-methylphenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-149    3-(1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-151    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-152    3-((3-ethoxypropoxy)(3-fluorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-153    N-(1-amino-3-cyclohexylpropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-154    3-((3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-155    3-(1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-156    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-157    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(5-methylthiazol-2-yl)pentyl)piperidine-1-carboxamide-   I-158    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-hydroxypropan-2-yl)piperidine-1-carboxamide-   I-159    3-((3-methoxypropoxy)(4-chloropyridin-2-yl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-160    3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-161    3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-162    3-(1-(2-(m-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-163    N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-165    3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-166    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-167    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide-   I-168    3-(1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-169    3-(1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-170    3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-171    3-(1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-172    N-(3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-173    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,5-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-174    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-ethylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-175    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,3-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-176    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(3,5-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-177    3-(1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-178    3-(1-(2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-179    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(3-methoxyphenyl)pentyl)piperidine-1-carboxamide-   I-180    3-(1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-181    3-(1-(3-chlorophenyl)-4-cyclopropyl-1-hydroxybutyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-182    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-183    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-184    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(5-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-185    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-186    N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-187    3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-188    3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide-   I-190    3-((3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-191    3-(1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-192    3-(1-(2-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-193    3-(1-(4-chloropyridin-2-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-194    3-((3-ethoxypropoxy)(phenyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-195    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-196    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-197    N-(3-cyclopentyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-198    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-199    3-(1-(2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-200    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(tetrahydro-2H-pyran-4-yl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-201    2-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-202    N-(3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-203    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-204    3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-205    3-(1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-206    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-207    3-(1-(5-chloro-1-methyl-1H-imidazol-2-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-208    3-(1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-209    3-(1-(3-chlorophenyl)-1-hydroxyethyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-210    3-(1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-211    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-1-(1H-indazol-7-yl)-5-methoxypentyl)piperidine-1-carboxamide-   I-212    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-1-(1H-indazol-7-yl)-5-methoxypentyl)piperidine-1-carboxamide-   I-213    3-(1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-214    3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-215    3-(1-(3-(o-tolyloxy)-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-216    3-(1-(2-(o-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-217    3-(1-(2-(5-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-218    3-(1-(2-(4-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-219    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-220    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-221    N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-222    3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-223    3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-224    3-(1-(2-(2-chlorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-225    3-(1-hydroxy-5-methoxy-1-(2-(neopentyloxy)phenyl)pentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-226    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(3-(methylthio)phenyl)pentyl)piperidine-1-carboxamide-   I-227    3-(4-(acetylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-228    3-(1-(2-(allyloxy)-5-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-229    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(5-fluoro-2-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-230    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-fluoro-6-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-231    3-(4-cyclopropyl-1-hydroxy-1-(2-phenoxyphenyl)butyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-232    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(5,5,5-trifluoro-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-233    3-(1-(3-chlorophenyl)-1,5-dimethoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-234    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide-   I-235    3-(1-(3-chlorophenyl)-1,5-dihydroxyheptyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-236    3-(4-cyclopropyl-1-(3-fluorophenyl)-1-hydroxybutyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-237    N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-238    3-((3-ethoxypropoxy)(m-tolyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-239    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-240    3-(1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-241    N-(3-cyclopropyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-242    3-(1-(2-(3-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-243    3-(1-(2-(4-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-244    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-245    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-246    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide-   I-247    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carbothioamide-   I-248    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(quinolin-8-yl)pentyl)piperidine-1-carboxamide-   I-249    3-(1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-250    3-(1-(3-chloro-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-251    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-252    3-(1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-253    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-254    3-(1-hydroxy-5-methoxy-1-(2-(pyridin-3-yloxy)phenyl)pentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-255    3-((3-ethoxypropoxy)(3-fluorophenyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-256    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-257    N-(3-cyclopentyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-258    3-(1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-hydroxy-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-259    3-(1-(3-fluoro-2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-260    3-(1-(2-(2-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-261    3-(1-(2-(3-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-262    3-(1-(2-(4-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-263    3-(1-(3-chlorophenyl)-5,5-difluoro-1-hydroxyhexyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-264    3-((3-methoxypropoxy)(2,3-dichlorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-265    3-(1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-266    3-((3-ethoxypropoxy)(2,3-dichlorophenyl)methyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-267    3-(1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-268    3-(1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-269    3-(1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-270    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(5-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-271    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N′-cyano-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamidine-   I-272    3-(1-acetamido-1-(3-fluorophenyl)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-273    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-274    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)benzamide-   I-275    3-(1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-276    3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-277    3-(1-(2-(benzyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-278    3-(1-(2-(m-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-279    3-(1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-280    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-281    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-282    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-283    3-(1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-284    3-(1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-285    3-((3-ethoxypropoxy)(2,3-dichlorophenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-286    3-(1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N-(3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-287    3-(1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-288    3-(1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-289    3-(1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-290    3-(1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-291    3-(1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-292    3-(1-(3-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-293    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-294    3-((3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-295    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-296    3-(1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-297    3-(1-(2-(4-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-298    3-(1-(2-(3-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-299    N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-300    2-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-301    3-(1-acetamido-1-(3-chlorophenyl)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-302    3-(1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-303    N-(4,4,4-trifluoro-1-(methylamino)butan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-304    3-(1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-305    N-(1-(2-methoxyethylamino)-3-cyclohexylpropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-306    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-307    3-(1-(2-(o-tolyloxy)-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-308    3-(1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-309    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide-   I-310    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-(trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide-   I-311    3-(1-(2-(p-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-312    3-(1-(2-(o-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-313    3-(1-(2-(5-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-314    3-(1-(2-(4-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-315    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-316    3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-317    3-(5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-318    3-(1-(2-(4-fluorophenoxy)-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-319    3-(1-(3,5-difluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-ylpiperidine-1-carboxamide-   I-320    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-321    3-((3-ethoxypropoxy)(3-chloro-2-fluorophenyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-322    3-(1-(3-chlorophenyl)-5-methoxy-1-(propionamido)pentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-323    N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-(1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-324    3-((3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-325    N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide-   I-326    3-(1-(3-hydroxypropoxy)-1-(3-chlorophenyl)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-327    N-(1-(2-ethoxyethylamino)-3-cyclohexylpropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-328    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-(pyridin-3-yloxy)phenyl)pentyl)piperidine-1-carboxamide-   I-329    3-(1-acetamido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-330    3-(1-(2-(allyloxy)-3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-331    N-(1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-332    3-(1-(3-chlorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-333    3-(5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)-N-(3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-334    N-(5,5,5-trifluoro-4-methyl-1-(methylamino)pentan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-335    3-(1-(2-(benzyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-336    3-(1-(3-chloro-2-fluorophenyl)-5-methoxy-1-(propionamido)pentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-337    3-(1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-ylpiperidine-1-carboxamide-   I-338    N-(3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-339    3-(1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-340    3-(1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-341    3-(1-(3-chlorophenyl)-1-hydroxypropyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-342    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-2-(5-methoxy-1-phenylpentyl)morpholine-4-carboxamide-   I-343    3-(1-(3-chlorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-345    3-(1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide-   I-346    3-(1-(3-chlorophenyl)-1-hydroxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-347    3-(1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-348    3-(1-(3-chlorophenyl)-1,4-dihydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-349    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-350    3-(1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-351    3-(1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-352    N-(3-amino-1-cyclohexylbutan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-353    N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-354    N-(2-amino-3-cyclohexylpropyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-356    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methoxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-357    3-(1-(3-cyanophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-358    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-359    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-360    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-361    3-(1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-362    3-(4-acetamido-1-(2-fluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-363    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-(3-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-364    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-(3-fluoro-4-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-366    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-(3-fluoro-2-hydroxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-367    N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-368    N-(3-amino-1-cyclohexylbutan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-369    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-370    N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-370    N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-371    N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-372    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-373    N-(2-amino-3-cyclohexylpropyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-374    3-(1-(benzofuran-4-yl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-375    3-(4-acetamido-1-(3,5-dimethylphenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-376    3-(1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-377    N-(2-amino-3-cyclohexylpropyl)-3-(1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-378    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methoxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-379    3-(1-(2-cyano-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-380    3-(1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-381    N-(2-amino-3-cyclohexylpropyl)-2-(1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxamide-   I-382    3-(4-acetamido-1-(3-fluoro-5-methylphenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-383    3-(4-acetamido-1-(2-fluoro-5-methylphenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-385    3-(1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-386    3-(1-(3-chloro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-387    3-(1-(3-chlorophenyl)-1,5-dimethoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-388    3-(4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-389    3-(4-acetamido-1-(3,5-difluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-390    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-391    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-392    3-(4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-393    3-((2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-395    N-(2-amino-3-tert-butoxypropyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-395    N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-396    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-397    N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-398    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-399    N-(3-amino-1-cyclohexylbutan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-400    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,3,4-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-401    N-(1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-(1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-402    3-(1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-402    3-(1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-403    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-404    2-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-405    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-406    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamide-   I-408    3-(1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-410    3-(1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-411    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-(2-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-412 methyl    3-(1-(1-(1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate-   I-413    2-(1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-416    3-(1-(3-chlorophenyl)-1-hydroxy-4-propionamidobutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-417    3-(1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-418    3-(1-(3-chlorophenyl)-1-hydroxy-4-(3-methylureido)butyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-421    N-(3-amino-1-cyclohexylbutan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-423    3-(4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-424    3-(4-acetamido-1-(3-chloro-5-fluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-425    3-(4-acetamido-1-(2-chloro-3-fluorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-426    3-(1-(3-chloro-2-fluorophenyl)-1,5-dimethoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-427    N-(3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-428    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-429    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-430    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-431    3-(1-acetamido-1-(3-chlorophenyl)-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide-   I-432    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-433    3-(1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-434    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-435    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-436    N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-437    2-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-438    3-(1-(3-chlorophenyl)-4-(cyclopropanecarboxamido)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-439    3-(4-butyramido-1-(3-chlorophenyl)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-440    3-(1-(3-chlorophenyl)-4-(3,3-dimethylureido)-1-hydroxybutyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-442    3-(1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-447    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cycloheptyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-449    3-(1-(3-chlorophenyl)-1-hydroxy-4-(methylsulfonamido)butyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-450    3-(1-(3-chlorophenyl)-1-hydroxy-4-(sulfamoylamino)butyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-451    3-(4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-452    3-(1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-(3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-454    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-(2,3-difluorophenyl)-5-methoxy-1-propionamidopentyl)piperidine-1-carboxamide-   I-455    3-(1-(3-chlorophenyl)-1-hydroxy-4-(2-methoxypropanamido)butyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-456    3-(1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-457    N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-458    2-(1-acetamido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-459    3-(1-(2-bromo-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-463    3-(1-(3-fluoro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-464    3-(1-(3-chlorophenyl)-1-hydroxy-4-(2,2,2-trifluoroacetamido)butyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-466    N-(1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-467    3-(1-(3′-chloro-6-fluorobiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-468    N-(1-(3,3-difluorocyclobutyl)-3-(methylamino)propan-2-yl)-3-(1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-469    3-(1-butyramido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-470    3-(1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-471    2-((3-chloro-2-fluorophenyl)(3-methoxypropoxy)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-472    N-(2-amino-5-methoxy-4,4-dimethylpentyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-473    N-(1-amino-5-methoxy-4,4-dimethylpentan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-474    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-475    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-476    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-477    N-(3-amino-4-cyclohexylbutan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-478    3-(1-(3-chloro-2-fluorophenyl)-1-fluoro-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-479    3-(1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamide-   I-480    3-(1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-481    3-(1-(3-chlorophenyl)-1-ethoxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-482    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-483    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-484    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-485    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-488    N-(3-amino-4-cyclohexyl-1-hydroxybutan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-489    N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-490    3-(1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-491    N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-492    N-(2-amino-3-(4,4-difluorocyclohexyl)propyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-493    N-(3-amino-1-(3-noradamantyl)-1-hydroxypropan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-495    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-497    3-(1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-498    3-(1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-499    N-(3-amino-1-(3-noradamantyl)-1-hydroxypropan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-502    3-((3-chlorophenyl)(2-hydroxyethoxy)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-503    N-(2-amino-3-cyclopentylpropyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-504    N-(2-amino-3-(tetrahydrofuran-2-yl)propyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-505    N-(1-amino-3-(tetrahydrofuran-2-yl)propan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-507    3-(1-(3-chlorophenyl)-2-(2-methoxyethoxy)ethyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-508    N-(2-amino-3-(tetrahydro-2H-pyran-4-yl)propyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-509    N-(1-amino-3-(tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-510    N-(1-amino-3-(3-methoxycyclobutyl)propan-2-yl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-511    N-(2-amino-3-(3-methoxycyclobutyl)propyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-512    N-(2-amino-3-cyclohexylpropyl)-3-(1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-513    N-(2-amino-3-(tetrahydrofuran-2-yl)propyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-514    N-(1-amino-3-(tetrahydrofuran-2-yl)propan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-515    N-(2-amino-4-phenylbutyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-520    N-(2-amino-4-cyclohexylbutyl)-3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-522    3-(1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-523    3-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide-   I-524    3-((3-chloro-2-fluorophenyl)(3-methoxypropoxy)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-525    N-(azetidin-3-ylmethyl)-3-(1-(3-fluoro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-526    N-(1-amino-3-(tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-527    N-(2-amino-3-(3-methoxycyclobutyl)propyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-528    N-(1-amino-3-(3-methoxycyclobutyl)propan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-531    3-((3-chlorophenyl)(2-propionamidoethoxy)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-533    N-(4-cyclohexylpiperidin-3-yl)-3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-534    3-(1-(3-chlorophenyl)-1,6-dihydroxyheptyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-536    N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((2,3-difluorophenyl)(2-propionamidoethoxy)methyl)piperidine-1-carboxamide-   I-537    3-(1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyacetamido)ethyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-541    N-(3-amino-1-cyclohexylbutan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-544    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide-   I-545    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-546    3-(4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-(3-amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamide-   I-547    3-((3-chloro-2-fluorophenyl)(2-propionamidoethoxy)methyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-548    3-(1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-549    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(4-(pentan-3-yloxy)piperidin-3-yl)piperidine-1-carboxamide-   I-551    N-(3-amino-1-(4-fluorocyclohexyl)-1-hydroxypropan-2-yl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-552    3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(3-noradamantyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-553    3-(1-acetamido-5-ethoxy-1-(3-fluorophenyl)pentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-554    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(3,4-difluorocyclopentyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-556    3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-558    3-(1-acetamido-1-(3-chlorophenyl)-5-ethoxypentyl)-N-(1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-559    N-(2-amino-3-(3-noradamantyl)l-3-hydroxypropyl)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

Another embodiment of the invention is each of the compounds listedbelow and their salts, especially their pharmaceutically acceptablesalts:

I-1a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-hydroxy-1-phenylpentyl)piperidine-1- carboxamide I-2a

3-((S)-3- methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)benzamide I-3a

(3R)-3-((R)-(2- cyclopropylethoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-4a

(3S)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-5a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-6a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-2-amino-3-cyclohexylpropyl)piperidine-1- carboxamide I-7a

(3R)-N-((S)-1-amino-3- cyclopentylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-8a

(2R)-2-((S)-(3- methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)morpholine-4-carboxamide I-9a

(3R)-N-((R)-3-tert-butoxy-1- aminopropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine- 1-carboxamide I-10a

(3R)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-11a

N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-(3-methoxypropoxy)(phenyl)methyl) benzamide I-12a

(3R)-N-((S)-1-amino-3-phenylpropan- 2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-13a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-hydroxy-1-phenylheptyl)piperidine-1- carboxamide I-14a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-15a

(3S)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1- carboxamide I-16a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-17a

(3R)-3-((R)-(3- ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-18a

(3R)-3-((R)-(4- methoxybutoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-19a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-20a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)-N-methylpiperidine-1- carboxamideI-21a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-4-methoxy-1- phenylbutyl)piperidine-1- carboxamide I-22a

(3R)-3-((R)-(3-methoxypropoxy)(4- fluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1- carboxamide I-23a

(3R)-3-((R)-(3-methoxypropoxy)(2- fluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1- carboxamide I-24a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-cyclohexyl-5- methoxypentyl)piperidine-1- carboxamide I-25a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-4-cyclopropyl-1-hydroxy-1- phenylbutyl)piperidine-1- carboxamide I-26a

(3R)-3-((R)-(3-methoxypropoxy)(3- cyanophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1- carboxamide I-27a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1- carboxamide I-27b

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1- carboxamide I-28a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- phenylpentyl)cyclohexanecarboxamide I-29a

(3R)-N-((2S)-1-amino-4- (trifluoromethyl)pentan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-30a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1- carboxamide I-31a

(3R)-3-((R)-(3- ethoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-32a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1- phenylpentyl)piperidine-1- carboxamide I-33a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-34a

(3R)-3-((S)-(3- ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)-3-methylpiperidine-1-carboxamideI-35a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-4-ethoxy-1-hydroxy-1- phenylbutyl)piperidine-1- carboxamide I-36a

(3R)-N-((S)-2-amino-5-methoxy-4,4- dimethylpentyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-37a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-(3-fluorophenyl)-5- methoxypentyl)piperidine-1- carboxamide I-38a

(R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-fluoro-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-39a

(3R)-3-((R)-(3-methoxypropoxy)(3- fluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-40a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-41a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-cyclohexyl-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-42a

(3R)-3-((R)-(3-methoxypropoxy)2,4- difluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-43a

(3R)-3-((R)-(3-methoxypropoxy)(3,4- difluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-44a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-phenoxyphenyl)pentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-45a

(3R)-3-((R)-(3-methoxypropoxy)(3- cyanophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-46a

(3R)-3-((R)-(3-methoxypropoxy)(2- allylphenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1- carboxamide I-47a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(propylamino)propan-2-yl)piperidine- 1-carboxamide I-48a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1- phenylpentyl)piperidine-1- carboxamide I-49a

(3R)-3-((R)-(3- propoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-50a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m- tolylpentyl)piperidine-1-carboxamide I-51a

(3R)-N-((S)-1-amino-5-methoxy-4,4- dimethylpentan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-52a

(2S)-N2-(1-((R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3- cyclohexylpropan-1,2-diamine I-53a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-54a

(3R)-N-((S)-2-amino-5-methoxy-4,4- dimethylpentyl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-55a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-56a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-phenyoxyphenyl)pentyl)-N-((S)-piperidin-3-yl)piperidine-1- carboxamide I-57a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-4,4,4-trifluoro-1-hydroxy-1-m- tolylbutyl)piperidine-1-carboxamide I-58a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-59a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-2-((S)-(3-methoxypropoxy)(phenyl)methyl) morpholino)cyclobut-3-ene-1,2-dione I-60a

4-((R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-1,2,5-thiadiazol-3-amine I-61a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-1-(butylamino)-3-cyclohexylpropan-2-yl)piperidine-1- carboxamide I-62a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(isobutylamino)propan-2- yl)piperidine-1-carboxamide I-63a

(R)-N-((S)-1-cyclohexyl-3- (dimethylamino)propan-2-yl)-3-((R)-5-ethoxy-1-hydroxy-1- phenylpentyl)piperidine-1- carboxamide I-64a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-65a

(3R)-3-((R)-(3-ethoxypropoxy)(3,4- difluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-66a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-67a

(3R)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-68a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3,4-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-69a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((S)-1-hydroxy-1-phenylheptyl)piperidin-1-yl)cyclobut- 3-ene-1,2-dione I-70a

3-((2S,3S)-3-amino-1- cyclohexylbutan-2-ylamino)-4-((R)-3- ((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-70b

3-((2S,3R)-3-amino-1- cyclohexylbutan-2-ylamino)-4-((R)-3- ((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-71a

3-((R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-4-(N-((S)-1-amino-3- cyclohexylpropan-2-yl)-N-methylamino)cyclobut-3-ene-1,2- dione I-72a

(3R)-3-((S)-1-(2-(p-tolyloxy)-5- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-73a

3-((S)-3-cyclohexyl-1- (methylamino)propan-2-ylamino)-4- ((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-74a

(3R)-3-((R)-(3-methoxypropoxy)(2- (trifluoromethyl)phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-75a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(4- fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-76a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(2- fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-77a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(isopentylamino)propan-2- yl)piperidine-1-carboxamide I-78a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(pentylamino)propan-2-yl)piperidine- 1-carboxamide I-79a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-1-(3-isopropylphenyl)-5- methoxypentyl)piperidine-1- carboxamideI-80a

(3R)-3-((S)-1-(3-chlorophenyl)-4,4,4-trifluoro-1-hydroxybutyl)-N-((S)-3- cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-81a

(3R)-3-((S)-1-(5-chloro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-82a

(R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-5-cyclopropyl-1-hydroxy-1- phenylpentyl)piperidine-1- carboxamide I-83a

(3R)-3-((R)-(3-methoxypropoxy)(2- phenylphenyl)methyl)-N-((S)-2-amino-3-cyclohexylpropyl)piperidine- 1-carboxamide I-84a

(3R)-3-((R)-(3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-85a

3-((S)-3-cyclohexyl-1- (ethylamino)propan-2-ylamino)-4- ((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-86a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-phenoxyphenyl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-87a

(3R)-N-((S)-1-amino-5-methoxy-4,4- dimethylpentan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-88a

(3R)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1- (3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-89a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(2,4- difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-90a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(3,4- difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-91a

(3R)-N-((S)-1- (carbamoylmethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3- fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-92a

3-((S)-3-cyclohexyl-1- (propylamino)propan-2-ylamino)-4- ((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-93a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-(trifluoromethyl)phenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-94a

3-((S)-3-cyclohexyl-1- (isobutylamino)propan-2-ylamino)-4-((R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-95a

3-((S)-3-(butylamino)-1- cyclohexylpropan-2-ylamino)-4-((R)- 3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-96a

(3R)-3-((S)-1-(2-(p-tolyloxy)-5- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-97a

(3R)-3-((S)-1-(5-chloro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-98a

3-((S)-3-cyclohexyl-1- (methylamino)propan-2-ylamino)-4-((R)-3-((R)-(3-ethoxypropoxy)(3,4- difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-99a

3-((S)-1-amino-3-cyclohexylpropan- 2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(2- (trifluoromethyl)phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-100a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)piperidine-1- carboxamideI-101a

3-((S)-1-cyclohexyl-3- (pentylamino)propan-2-ylamino)-4- ((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl) piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-102a

3-((S)-1-cyclohexyl-3- (isopentylamino)propan-2-ylamino)-4-((R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-103a

(3R)-3-((S)-1-(2-(p-tolyloxy)-5- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidin-1-carboxamide I-104a

(3R)-3-((S)-1-(5-chloro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-105a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)- (pent-4-enyloxy)(phenyl)methyl)benzamide I-106a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-5-methoxy-1-phenylpentyl)benzamide I-107a

3-((S)-(2- ethoxyethoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan- 2-yl)benzamide I-108a

(3R)-3-((S)-1-(2- (cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-109a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- m-tolylpentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine- 1-carboxamide I-110a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-5-methoxy-1-(thiophen-2- yl)pentyl)piperidine-1-carboxamide I-111a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1,1,1-trifluoro-2-hydroxy-6- methoxyhexan-2-yl)piperidine-1- carboxamideI-112a

3-((S)-(2- (acetylamino)ethoxy)(phenyl)methyl)- N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)benzamide I-113a

(3R)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan- 2-yl)piperidine-1-carboxamide I-114a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-hydroxy-5-methoxy-1- phenylpentyl)benzamide I-115a

3-((S)-(3- ethoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)benzamide I-116a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-117a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-118a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-119a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(pyridin-2- yl)pentyl)piperidine-1-carboxamideI-120a

(3R)-3-((S)-1-(2-(2- cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-121a

(3R)-3-((S)-1-(2- (cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-122a

(3R)-3-((R)-(3- methoxypropoxy)(phenyl)methyl)-N- ((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine- 1-carbothioamide I-123a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-124a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-(neopentyloxy)phenyl)pentyl)-N-((S)-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-125a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(1-methyl-1H- imidazol-2-yl)phenyl)piperidine-1-carboxamide I-126a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiophen-2- yl)pentyl)piperidine-1-carboxamideI-127a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiophen-3- yl)pentyl)piperidine-1-carboxamideI-128a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-hydroxy-5-methoxy-1-m- tolylpentyl)benzamide I-129a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-o- tolylpentyl)benzamide I-130a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiazol-2- yl)pentyl)piperidine-1-carboxamideI-131a

(3R)-3-((S)-1-(2-(3- methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-132a

(3R)-3-((S)-1-(2-(4- methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-133a

(3R)-3-((S)-1-(2-(2- methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-134a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan- 2-yl)piperidine-1-carboxamide I-135a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan- 2-yl)piperidine-1-carboxamide I-136a

(R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-1- hydroxy-5-methoxypentyl)-N-(2-aminoethyl)-N-methylpiperidine-1- carboxamide I-137a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5- methoxypentyl)benzamide I-138a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-(4-fluorophenyl)-1-hydroxy-5- methoxypentyl)benzamide I-139a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (quinolin-8-yl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-140a

(3R)-3-((S)-1-(2-(2- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-141a

(3R)-3-((S)-1-(3-fluoro-2- phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-142a

(3R)-3-((S)-1-(2-(3- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-143a

(3R)-3-((S)-1-(2-(4- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-144a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-methylbenzofuran-7-yl)pentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-145a

(3R)-3-((S)-1-hydroxy-1-(2- isobutylbenzofuran-7-yl)-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-146a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-hydroxy-5-methoxy-1-phenylpentyl)- 3-methylpiperidine-1-carboxamideI-147a

(3R)-3-((S)-1-(2- (cyclopentylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-148a

(3S)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((R)-1-(2-fluoro-5-methylphenyl)-5- methoxypentyl)piperidine-1- carboxamideI-149a

(3R)-3-((S)-1-(benzo[b]thiophen-7- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-151a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-152a

(3R)-3-((R)-(3-ethoxypropoxy)(3- fluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-153a

(3R)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-154a

(3R)-3-((R)-(3-ethoxypropoxy)(3- chlorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-155a

(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-156a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-157a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(5- methylthiazol-2-yl)pentyl)piperidine-1-carboxamide I-158a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-hydroxypropan-2- yl)piperidine-1-carboxamide I-159a

(3R)-3-((R)-(3-methoxypropoxy)(4- chloropyridin-2-yl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidin-1-carboxamide I-160a

(R)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)-N-(2-methyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-161a

(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-162a

(3R)-3-((S)-1-(2-(m-tolyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-163a

(3R)-N-((S)-3-(3,3- difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((S)-1- (3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-165a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-166a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl- 1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-167a

3-((S)-1-(3-chlorophenyl)-1-hydroxy- 5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)benzamide I-168a

(3R)-3-((S)-1-(2-(4- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-169a

(3R)-3-((S)-1-(5-fluoro-2- phenpxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-170a

(3R)-3-((S)-1-(2-(3- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-171a

(3R)-3-((S)-1-(2-(2- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-172a

(3R)-N-((S)-3-cyclopentyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-173a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methyoxy-1-(2,5- dimethylphenyl)pentyl)piperidine-1-carboxamide I-174a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-ethylphenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-175a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3- dimethylphenyl)pentyl)piperidine-1-carboxamide I-176a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3,5- dimethylphenyl)pentyl)piperidine-1-carboxamide I-177a

(3R)-3-((S)-1-(2-(2- chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-178a

(3R)-3-((S)-1-(2-(4- chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-179a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3- methoxyphenyl)pentyl)piperidine-1- carboxamideI-180a

(3R)-3-((S)-1-(2- (cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxyphenyl)-N-((S)-4- methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-181a

(3R)-3-((S)-1-(3-chlorophenyl)-4- cyclopropyl-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-182a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-5-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-183a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-5-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-184a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-185a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-186a

(3R)-N-((1R,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-186b

(3R)-N-((1S,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-187a

(3R)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(1-hydroxycyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-188a

(3R)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(1-hydroxycyclohexyl)-2- (methylamino)propyl)piperidine-1- carboxamideI-190a

(3R)-3-((R)-(3-ethoxypropoxy)(3- chlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-191a

(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-192a

(3R)-3-((S)-1-(2-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-193a

(3R)-3-((S)-1-(4-chloropyridin-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3- cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-194a

(3R)-3-((R)-(3- ethoxypropoxy)(phenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-195a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3,5-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-196a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-197a

(3R)-N-((S)-3-cyclopentyl-1- (methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1- hydroxypentyl)piperidine-1- carboxamideI-198a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-199a

(3R)-3-((S)-1-(2-phenylphenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-200a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(tetrahydro-2H-pyran-4-yl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-201a

(2R)-2-((R)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)morpholine-4-carboxamide I-202a

(3R)-N-((1R,2R)-3-amino-1- cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-202b

(3R)-N-((1S,2R)-3-amino-1- cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-203a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((1R,2R)-1-cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-203b

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-204a

(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-205a

(3R)-3-((S)-1-(2-(2- ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-206a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-206b

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-3-cyclopentyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-207a

(3R)-3-((S)-1-(5-chloro-1-methyl-1H- imidazol-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-208a

(3R)-3-((S)-1-(2,2- difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4- methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-209a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxyethyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-210a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-211a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-1-(1H-indazol-7-yl)-5- methoxypentyl)piperidine-1- carboxamideI-212a

(3R)-3-((R)-(3-methoxypropoxy)(2,3- dichlorophenyl)methyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-213a

(3R)-3-((S)-1-(2-(4- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-214a

(3R)-3-((S)-1-(2-(3- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-215a

(3R)-3-((S)-1-(3-(o-tolyloxy)-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-216a

(3R)-3-((S)-1-(2-(o-tolyloxy)-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-217a

(3R)-3-((S)-1-(2-(5-fluoro-2- methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-218a

(3R)-3-((S)-1-(2-(4-fluoro-2- methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-219a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-220a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(3,3-difluorocyclobutyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-221a

(3R)-N-((S)-3-(3,3- difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((S)-1- (2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-222a

(3R)-3-((S)-1-(2- (cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-223a

(3R)-3-((S)-1-(2-(2- cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4- methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-224a

(3R)-3-((S)-1-(2-(2- chlorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-225a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-(neopentyloxy)phenyl)pentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-226a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3- (methylthio)phenyl)pentyl)piperidine-1-carboxamide I-227a

(3R)-3-((S)-4-(acetylamino)-1-(3- chlorophenyl)-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-228a

(3R)-3-((S)-1-(2-(allyloxy)-5- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-229a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methoxyphenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-230a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-6-methoxyphenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-231a

(3R)-3-((S)-4-cyclopropyl-1-hydroxy- 1-(2-phenoxyphenyl)butyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-232a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((2S)-5,5,5-trifluoro-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-233a

(3R)-3-((S)-1-(3-chlorophenyl)-1,5- dimethoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-234a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(ethylamino)propan-2- yl)piperidine-1-carboxamide I-235a

(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyheptyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-236a

(3R)-3-((S)-4-cyclopropyl-1-(3- fluorophenyl)-1-hydroxybutyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-237a

(3R)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide I-238a

(3R)-3-((R)-(3-ethoxypropoxy)(m- tolyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-239a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-ethoxy-1- hydroxypentyl)piperidine-1- carboxamideI-240a

(3R)-3-((S)-1-(2-fluoro-3- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-240b

(3R)-3-((S)-1-(2-fluoro-3- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-241a

(3R)-N-((S)-3-cyclopropyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)piperidine-1- carboxamideI-242a

(3R)-3-((S)-1-(2-(3- methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-243a

(3R)-3-((S)-1-(2-(4- methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-244a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-244b

(3R)-3-((S)-1(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-245a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(1-hydroxycyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-246a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(1-hydroxycyclohexyl)-2- (methylamino)propyl)piperidine-1- carboxamideI-247a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-248a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(quinolin-8- yl)pentyl)piperidine-1-carboxamideI-249a

(3R)-3-((S)-1-(2-(p-tolyloxy)-5- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-250a

(3R)-3-((S)-1-(3-chloro-5- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-251a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-252a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclopentyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-253a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(trans-4-fluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-254a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-(pyridin-3-yloxy)phenyl)pentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piepridine- 1-carboxamideI-255a

(3R)-3-((R)-(3-ethoxypropoxy)(3- fluorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-256a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-257a

(3R)-N-((S)-3-cyclopentyl-1- (methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1- hydroxypentyl)piperidine-1-carboxamide I-258a

(3R)-3-((S)-1-(2-(2- ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-3-hydroxy-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-259a

(3R)-3-((S)-1-(3-fluoro-2- phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-260a

(3R)-3-((S)-1-(2-(2- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-261a

(3R)-3-((S)-1-(2-(3- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-262a

(3R)-3-((S)-1-(2-(4- fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-263a

(3R)-3-((S)-1-(3-chlorophenyl)-5,5- difluoro-1-hydroxyethyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-264a

(3R)-3-((R)-(3-methoxypropoxy)(2,3- dichlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-265a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-266a

(3R)-3-((R)-(3-ethoxypropoxy)(2,3- dichlorophenyl)methyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-267a

(3R)-3-((S)-1-(benzo[b]thiophen-7- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-268a

(3R)-3-((S)-1-(benzo[b]thiophen-2- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-269a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (3-(trifluoromethoxy)phenyl)pentyl)-N-((S)-4,4-dimethyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-270a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(5-fluorobenzofuran-7-yl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-271a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N′-cyano-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-272a

(3R)-3-((S)-1-acetamido-1-(3- fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-273a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(3,3- difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-274a

N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(3-(trifluoromethyl)phenyl)-1-hydroxy- 5-methoxypentyl)benzamide I-275a

(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-276a

(3R)-3-((S)-1-hydroxy-5-methoxy-1- (2-phenoxyphenyl)pentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2- yl)piepridine-1-carboxamide I-277a

(3R)-3-((S)-1-(2-benzyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-278a

(3R)-3-((S)-1-(2-(m-tolyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-279a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-280a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)-3-(trans-4-methylcyclohexyl)propan-2- yl)piperidine-1-carboxamide I-281a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-(trifluoromethyl)phenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-282a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1- hydroxypentyl)piperidine-1-carboxamide I-283a

(3R)-3-((S)-1-(2-fluoro-3- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-284a

(3R)-3-((S)-1-(2,3-dichlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-285a

(3R)-3-((R)-(3-ethoxypropoxy)(2,3- dichlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-286a

(3R)-3-((S)-1-(2,3-dichlorophenyl)-5- ethoxy-1-hydroxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-287a

(3R)-3-((S)-1-(2-(4- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-288a

(3R)-3-((S)-1-(5-fluoro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-289a

(3R)-3-((S)-1-(2-(3- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-290a

(3R)-3-((S)-1-(2-(2- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-291a

(3R)-3-((S)-1-(3-fluoro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-292a

(3R)-3-((S)-1-(3-(4- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-293a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-294a

(3R)-3-((R)-(3-ethoxypropoxy)(3- chlorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-295a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(trans-4- fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-296a

(3R)-3-((S)-1-(2-(2- chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-296b

(3R)-3-((1R)-1-(2′-chlorobiphenyl-2- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-297a

(3R)-3-((S)-1-(2-(4- chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-298a

(3R)-3-((S)-1-(2-(3- chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-299a

(3R)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1- (2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-300a

(2R)-2-((R)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)morpholine-4-carboxamide I-301a

(3R)-3-((S)-1-acetamido-1-(3- chlorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-302a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-303a

(3R)-N-((S)-4,4,4-trifluoro-1- (methylamino)butan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)piperidine-1- carboxamideI-304a

(3R)-3-((S)-1-(2-(2- (trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-305a

(3R)-N-((S)-1-(2- methoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-306a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)- 1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-307a

(3R)-3-((S)-1-(2-(o-tolyloxy)-3- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-308a

(3R)-3-((S)-1-(2,3-difluorophenyl)-5- ethoxy-1-hydroxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-309a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3- (trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide I-310a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- (trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide I-311a

(3R)-3-((S)-1-(2-(p-tolyloxy)-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-312a

(3R)-3-((S)-1-(2-(o-tolyloxy)-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-313a

(3R)-3-((S)-1-(2-(5-fluoro-2- methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-314a

(3R)-3-((S)-1-(2-(4-fluoro-2- methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-315a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(2-(cyclopenyloxy)phenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-316a

(3R)-3-((S)-1-(2-(2- cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3- cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-317a

(3R)-3-((S)-5-ethoxy-1-(2,3- difluorophenyl)-1-hydroxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-318a

(3R)-3-((S)-1-(2-(4-fluorophenoxy)-5- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-319a

(3R)-3-((S)-1-(3,5-difluoro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-320a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-321a

(3R)-3-((R)-(3-ethoxypropoxy)(3- chloro-2-fluorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-322a

(3R)-3-((S)-1-(3-chlorophenyl)-5- methoxy-1-(propionamido)pentyl)-N-((S)-3-cyclohexyl)-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-323a

(3R)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1- (2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-324a

(3R)-3-((R)-(3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)-N-((S)-3-(4,4- difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-325a

(3R)-N-((S)-3-(3,3- difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((R)-1- hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl) piperidine-1-carboxamide I-326a

(3R)-3-((S)-1-(3-hydroxypropoxy)-1- (3-chlorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-327a

(3R)-N-((S)-1-(2-ethoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-328a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-(pyridin-3- yloxy)phenyl)pentyl)piperidine-1-carboxamide I-329a

(3R)-3-((R)-1-acetamido-1-(3-chloro- 2-fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-329b

(3R)-3-((S)-1-acetamido-1-(3-chloro- 2-fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-330a

(3R)-3-((S)-1-(2-(allyloxy)-3- bromophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-331a

(3R)-N-((S)-1-(2,2,2- trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-332a

(3R)-3-((S)-1-(3-chlorophenyl)-1- (isobutyramido)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-333a

(3R)-3-((S)-5-ethoxy-1-(2,3,5- trifluorophenyl)-1-hydroxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-334a

(3R)-N-((2S)-5,5,5-trifluoro-4-methyl-1-(methylamino)pentan-2-yl)-3-((S)- 1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1- carboxamide I-335a

(3R)-3-((S)-1-(2-(benzyloxy)phenyl)- 1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-336a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-5-methoxy-1-(propionamido)pentyl)-N-((S)-3- cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-337a

(3R)-3-((S)-1-(2-(4- fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-338a

(3R)-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-phenoxyphenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-339a

(3R)-3-((S)-1-(2-(2- (trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4- methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-340a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-340b

(3R)-3-((R)-1-(3-chloro-2- fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-((S)-3-cyclohexyl- 1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-341a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxypropyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-342a

(S)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-2-((R)-5-methoxy-1-phenylpentyl)morpholine- 4-carboxamide I-343a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-345a

3-((R)-1-cyclohexyl-1-hydroxy-5- methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)benzamide I-346a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-347a

(3R)-3-((R)-1-cyclohexyl-1-hydroxy- 5-methoxypentyl-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-348a

(3R)-3-((S)-1-(3-chlorophenyl)-1,4- dihydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-349a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((2R,3S)-3-hydroxy-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-350a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan- 2-yl)piperidine-1-carboxamide I-351a

(3R)-3-((S)-1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N- ((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-352a

(3R)-N-((2S,3S)-3-amino-1- cyclohexylbutan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-353a

(3R)-N-((1S,2R)-1-cyclopentyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-354a

(3R)-N-((S)-2-amino-3- cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-356a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-4-methoxy-4-methyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-357a

(3R)-3-((S)-1-(3-cyanophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-358a

(3R)-3-((R)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl- 1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-359a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimthyl- 1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-360a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3- hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine- 1-carboxamide I-361a

(3R)-3-((S)-1-(benzo[b]thiophen-4- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1- (methylamino)pentan-2-yl)piperidine- 1-carboxamideI-362a

(3R)-3-((S)-4-acetamido-1-(2- fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-363a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-363b

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((R)-1-(3-fluoro-2-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-364a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-4-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-364b

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((R)-1-(3-fluoro-4-methylphenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-366a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-hydroxyphenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-367a

(3R)-N-((1S,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-368a

(3R)-N-((2S,3R)-3-amino-1- cyclohexylbutan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-369a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-2- (methylamino)propyl)piperidine-1- carboxamide I-370a

(3R)-N-((S)-1-(cis-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1- (2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-370b

(3R)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1- (2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-370c

(3R)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((R)-1- (2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-371a

(3R)-N-((1S,2R)-1-cyclopentyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-372a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclopentyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-373a

(3R)-N-((S)-2-amino-3- cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-374a

(3R)-3-((S)-1-(benzofuran-4-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-375a

(3R)-3-((S)-4-acetamido-1-(3,5- dimethylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-376a

(3R)-3-((R)-1-cyclohexyl-1-hydroxy- 5-methoxypentyl)-N-((S)-1-(4,4-difluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-377a

(3R)-N-((S)-2-amino-3- cyclohexylpropyl)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5- methoxyphenyl)piperidine-1-carboxamide I-378a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methoxy-4- methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-379a

(3R)-3-((S)-1-(2-cyano-5- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-380a

(3R)-3-((S)-1-(3-carbamoylphenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-381a

(3R)-N-((S)-2-amino-3- cyclohexylpropyl)-2-((R)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5- methoxypentyl)morpholine-4-carboxamide I-382a

(3R)-3-((S)-4-acetamido-1-(3-fluoro- 5-methylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-383a

(3R)-3-((S)-4-acetamido-1-(2-fluoro- 5-methylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-385a

(3R)-3-((S)-1-(2- (cyclopropylmethoxy)-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-386a

(3R)-3-((S)-1-(3-chloro-2- methylphenyl)-1-hydroxy-5-mthoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-386b

(3R)-3-((R)-1-(3-chloro-2- methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-387a

(3R)-3-((S)-1-(3-chlorophenyl)-1,5- dimethoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-388a

(3R)-3-((S)-4-acetamido-1-(2,3- difluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-389a

(3R)-3-((S)-4-acetamido-1-(3,5- difluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-390a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)-3-(4- methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide I-391a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-hydroxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-391b

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-392a

(3R)-3-((S)-4-acetamido-1-(2,3- difluorophenyl)-1-hydroxybutyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-393a

(3R)-3-((S)-(2-acetamidoethoxy)(3- chloro-2-fluorophenyl)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-393b

(3R)-3-((R)-(2-acetamidoethoxy)(3- chloro-2-fluorophenyl)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-394a

(3R)-N-((R)-2-amino-3-tert- butoxypropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-395a

(3R)-N-((1S,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-396a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-hydroxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-396b

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-397a

(3R)-N-((1S,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,5-difluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-398a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-399a

(3R)-N-((2S,3R)-3-amino-1- cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidin-1-carboxamide I-400a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,4- trifluorophenyl)pentyl)piperidine-1-carboxamide I-401a

(3R)-N-((S)-1-(4,4- difluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1- (2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-402a

(3R)-3-((S)-1-(2,5-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-402b

(3R)-3-((S)-1-(2,5-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-403a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-403b

(3R)-3-((R)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-404a

(R)-2-((R)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)morpholine-4-carboxamide I-405a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1- cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-406a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- (methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1- carboxamide I-406b

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1- (methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1- carboxamide I-408a

(3R)-3-((S)-1-(benzo[b]thiophen-4- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-410a

(3R)-3-((S)-1-(benzofuran-7-yl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-411a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(2-fluorobenzofuran-7-yl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-412a

methyl 3-((S)-1-((R)-1-((S)-1- cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)-1- hydroxy-5-methoxypentyl)benzoate I-413a

(3R)-2-((R)-1-(benzo[b]thiophen-7- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)morpholine-4-carboxamideI-416a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-propionamidobutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-417a

(3R)-3-((S)-1-(2- (cyclopropylmethoxy)-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl- 1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-418a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-(3-methylureido)butyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-421a

(3R)-N-((2S,3S)-3-amino-1- cyclohexylbutan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-423a

(3R)-3-((S)-4-acetamido-1-(3-chloro- 2-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-424a

(3R)-3-((S)-4-acetamido-1-(3-chloro- 5-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-425a

(3R)-3-((S)-4-acetamido-1-(2-chloro- 3-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-426a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1,5-dimethoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-427a

(3R)-N-((2R,3S)-3-hydroxy-4-methyl- 1-(methylamino)pentan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)piperidine-1- carboxamideI-428a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1- cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-429a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-429b

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-430a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1- cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-431a

3-((S)-1-acetamido-1-(3- chlorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)benzamide I-432a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-432b

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-433a

(3R)-3-((S)-1-(3-chloro-2,4- difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-433b

(3R)-3-((R)-1-(3-chloro-2,4- difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-434a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-435a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-435b

(3R)-3-((R)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-436a

(3R)-N-((S)-1-(cis-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1- carboxamide I-437a

(3R)-2-((R)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2- yl)morpholine-4-carboxamide I-438a

(3R)-3-((S)-1-(3-chlorophenyl)-4- (cyclopropanecarboxamido)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-439a

(3R)-3-((S)-4-butyramido-1-(3- chlorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-440a

(3R)-3-((S)-1-(3-chlorophenyl)-4-(3,3-dimethylureido)-1-hydroxybutyl)-N- ((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-442a

(3R)-3-((S)-1-(3-bromophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-447a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1- cycloheptyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-449a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-(methylsulfonylamido)butyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-450a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-(sulfamoylamino)butyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-451a

(3R)-3-((S)-4-acetamido-1-(2,3- difluorophenyl)-1-hydroxybutyl)-N-((S)-1-(4,4-difluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-452a

(3R)-3-((S)-1-(3-fluoro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3- hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine- 1-carboxamide I-454a

(3R)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-methoxy-1- propionamidopentyl)piperidine-1-carboxamide I-455a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-((R)-2-methoxypropanamido)butyl)-N-((S)- 1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-455b

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-((S)-2-methoxypropanamido)butyl)-N-((S)- 1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-456a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-2-(2-methoxyethoxy)ethyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-457a

(3R)-N-((1S,2R)-1-cyclopentyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2- phenoxyphenyl)pentyl)piperidine-1-carboxamide I-458a

2-((R)-1-acetamido-1-(3-chloro-2- fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)morpholine-4-carboxamideI-459a

(3R)-3-((S)-1-(2-bromo-5- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-463a

(3R)-3-((S)-1-(3-fluoro-2-(o- tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3- hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine- 1-carboxamide I-464a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-4-(2,2,2-trifluoroacetamido)butyl)-N-((S)-1- cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-466a

(3R)-N-((1S,2R)-1-cyclopentyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2- phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-467a

(3R)-3-((S)-1-(3′-chloro-6- fluorobiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclopentyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-468a

(3R)-N-((S)-1-(3,3- difluorocyclobutyl)-3-(methylamino)propan-2-yl)-3-((S)-1- (3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine- 1-carboxamide I-469a

(3R)-3-((S)-1-butyramido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N- ((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-470a

(S)-3-((R)-1-(3-chloro-2- fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine- 1-carboxamideI-471a

(3R)-2-((S)-(3-chloro-2- fluorophenyl)(3-methoxypropoxy)methyl-N-((S)-1- cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide I-472a

(3R)-N-((S)-2-amino-5-methoxy-4,4- dimethylpentyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-473a

(3R)-N-((S)-1-amino-5-methoxy-4,4- dimethylpentan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-474a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3- (methylamino)butan-2-yl)piperidine-1-carboxamide I-475a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl- 2-(methylamino)propyl)piperidine-1-carboxamide I-476a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(1-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-476b

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((R)-1-(1-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-477a

(3R)-N-((2R,3S)-3-amino-4- cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-477b

(3R)-N-((2S,3S)-3-amino-4- cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-478a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-fluoro-5-methoxypentyl)-N-((S)-1-cyclohexyl- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-479a

(3R)-3-((S)-1-benzo[b]thiophen-7- yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine- 1-carboxamide I-480a

(3R)-3-((S)-1-(2,3- dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-481a

(3R)-3-((S)-1-(3-chlorophenyl)-1- ethoxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-482a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxy-4- methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-483a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxy-4- methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-484a

(3R)-3-((S)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-methoxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-484b

(3R)-3-((R)-1-(2,3-difluorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-methoxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-485a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1- cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide I-485b

(3R)-3-((R)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1- cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide I-488a

(3R)-N-((2S,3S)-3-amino-4- cyclohexyl-1-hydroxybutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-489a

(3R)-N-((1S,2R)-1-cyclohexyl-1- hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1- (2,3,5-trifluorophenyl)pentyl)piperidine-1- carboxamide I-490a

(3R)-3-((S)-1-(2-chloro-3- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-491a

(3R)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1- carboxamide I-492a

(3R)-N-((S)-2-amino-3-(4,4- difluorocyclohexyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-493a

(3R)-N-((1S,2R)-3-amino-1-(3- noradamantyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-495a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-497a

(3R)-3-((S)-1-(3-chloro-2,4- difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1- cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-498a

(3R)-3-((S)-1-(3-chloro-2,4- difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4- fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine- 1-carboxamide I-499a

(3R)-N-((1S,2R)-(3-amino-1-(3- noradamantyl)-1-hydroxy)propan-2-yl)-3-((S)-1-(2-fluoro-3-chlorophenyl)- 1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-502a

(3R)-3-((R)-(3-chlorophenyl)(2- hydroxyethoxy)methyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamide I-503a

(3R)-N-((S)-2-amino-3- cyclopentylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-504a

(3R)-N-((2S)-2-amino-3- (tetrahydrofuran-2-yl)propyl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-505a

(3R)-N-((2S)-1-amino-3- (tetrahydrofuran-2-yl)propan-2-yl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-507a

(3S)-3-((R)-1-(3-chlorophenyl)-2- (2-methoxyethoxy)ethyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-508a

(3R)-N-((S)-2-amino-3- (tetrahydro-2H-pyran-4- yl)propyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-509a

(3R)-N-((2S)-1-amino-3- (tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-510a

(3R)-N-((S)-1-amino-3-(3- methoxycyclobutyl)propan-2-yl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-511a

(3R)-N-((S)-2-amino-3-(trans-3- methoxycyclobutyl)propyl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-511b

(3R)-N-((S)-2-amino-3-(cis-3- methoxycyclobutyl)propyl)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-512a

(S)-N-((S)-2-amino-3- cyclohexylpropyl)-3-((R)-1-(3-chloro-2-fluorophenyl)-5- methoxypentyl)piperidine-1- carboxamide I-512b

(S)-N-((S)-2-amino-3- cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-5- methoxypentyl)piperidine-1- carboxamide I-513a

(3R)-N-((2S)-2-amino-3- (tetrahydrofuran-2-yl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)- 1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-514a

(3R)-N-((2S)-1-amino-3- (tetrahydrofuran-2-yl)propan-2-yl)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-515a

(3R)-N-((S)-2-amino-4- phenylbutyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-520a

(3R)-N-((S)-2-amino-4- cyclohexylbutyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-522a

(S)-3-((R)-1-(3-chloro-2- fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-522b

(S)-3-((S)-1-(3-chloro-2- fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-523a

(3R)-3-((S)-1-(6-fluoro-3′- methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)- piperidin-3-yl)piperidine-1- carboxamide I-524a

(3R)-3-((R)-(3-chloro-2- fluorophenyl)(3- methoxypropoxy)methyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-525a

(3R)-N-(azetidin-3-ylmethyl)-3- ((S)-1-(3-fluoro-2-(o-tolyloxy)phenyl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-526a

(3R)-N-((2S)-1-amino-3- (tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-((S)-1-(3- chloro-2-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-527a

(3R)-N-((S)-2-amino-3-(3- methoxycyclobutyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)- 1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-528a

(3R)-N-((S)-1-amino-3-(3- methoxycyclobutyl)propan-2-yl)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-531a

(3R)-3-((R)-(3-chlorophenyl)(2- propionamidoethoxy)methyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-533a

(3R)-N-((3S,4S)-4- cyclohexylpiperidin-3-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy- 5-methoxypentyl)piperidine-1-carboxamide I-534a

(3R)-3-((1S)-1-(3-chlorophenyl)- 1,6-dihydroxyheptyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamide I-536a

(3R)-N-((2S)-1-cyclohexyl-3- (methylamino)propan-2-yl)-3-((R)-(2,3-difluorophenyl)(2- propionamidoethoxy)methyl)piperidine-1-carboxamide I-537a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-2-(2-methoxyacetamido)ethyl)-N-((S)- 1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-541a

(3R)-N-((2S,3S)-3-amino-1- cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1- hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-544a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3S,4S)-4- cyclohexylpiperidin-3-yl)piperidine-1-carboxamide I-545a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- methoxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-545b

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- methoxycyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-546a

(3R)-3-((S)-4-acetamido-1-(3- choloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3- amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamide I-546b

(3R)-3-((R)-4-acetamido-1-(3- chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3- amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamide I-547a

(3R)-3-((R)-(3-chloro-2- fluorophenyl)(2- propionamidoethoxy)methyl)-N-((2S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-548a

(3R)-3-((S)-1-(2,3- difluorophenyl)-1-hydroxy-5-methoxyphenyl)-N-((S)-1-(cis-4- methoxycyclohexyl)-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-549a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3R,4R)-4- (pentan-3-yloxy)piperidin-3-yl)piperidine-1-carboxamide I-551a

(3R)-N-((1S,2R)-3-amino-1- (trans-4-fluorocyclohexyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3- chloro-2-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-552a

(3R)-3-((S)-1-(3-chlorophenyl)-1- hydroxy-5-methoxypentyl)-N-((2S)-1-(3-noradamantyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-553a

(3R)-3-((S)-1-acetamido-5- ethoxy-1-(3-fluorophenyl)pentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-554a

(R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1- ((1r,3R,4S)-3,4- difluorocyclopentyl)-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-556a

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4- methoxycyclohexyl)-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-556b

(3R)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans- 4-methoxycyclohexyl)-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-558a

(3R)-3-((S)-1-acetamido-1-(3- chlorophenyl)-5-ethoxypentyl)-N-((S)-1-cyclohexyl-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-559a

(3R)-N-((2R,3S)-2-amino-3-(3- noradamantyl)-3-hydsroxypropyl)-3-((S)-1-(3-chloro-2- fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide

The following are preferred compounds of Formula I:

-   I-14a    (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-15a    (3S)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-19a    N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-27a    (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-31a    (3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-32a    (3R)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-33a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-37a    (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-(3-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-40a    (3R)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-41a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-41b    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-48a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide-   I-50a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-50a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-53a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-53a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-64a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-66a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-67a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide-   I-68a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-86a    (3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-86a    (3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-88a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-93a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-93a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-96a    (3R)-3-((S)-1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-97a    (3R)-3-((S)-1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-110a    (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-(thiophen-2-yl)pentyl)piperidine-1-carboxamide-   I-117a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-118a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-123a    (3R)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-134a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-135a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-144a    (3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-methylbenzofuran-7-yl)pentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-148a    (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-(2-fluoro-5-methylphenyl)-5-methoxypentyl)piperidine-1-carboxamide-   I-149a    (3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-151a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-152a    (3R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-153a    (3R)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-154a    (3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide-   I-155a    (3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-161a    (3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-162a    (3R)-3-((S)-1-(2-(m-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-165a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-166a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-172a    (3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-173a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,5-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-174a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-ethylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-175a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-176a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3,5-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-179a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-methoxyphenyl)pentyl)piperidine-1-carboxamide-   I-180a    (3R)-3-((S)-1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-181a    (3R)-3-((S)-1-(3-chlorophenyl)-4-cyclopropyl-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-182a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-183a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-184a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-185a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-186b    (3R)—N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-190a    (3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-192a    (3R)-3-((S)-1-(2-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-193a    (3R)-3-((S)-1-(4-chloropyridin-2-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-194a    (3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-195a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-196a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-197a    (3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-198a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-201a    (2R)-2-((R)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-202a    (3R)—N-((1R,2R)-3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-202b    (3R)—N-((1S,2R)-3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-203b    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-206a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-208a    (3R)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-210a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-211a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-1-(1H-indazol-7-yl)-5-methoxypentyl)piperidine-1-carboxamide-   I-216a    (3R)-3-((S)-1-(2-(o-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-217a    (3R)-3-((S)-1-(2-(5-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-219a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-221a    (3R)—N—((S)-3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-223a    (3R)-3-((S)-1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-224a    (3R)-3-((S)-1-(2-(2-chlorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-226a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-(methylthio)phenyl)pentyl)piperidine-1-carboxamide-   I-227a    (3R)-3-((S)-4-(acetylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-229a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-230a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-6-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-234a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide-   I-237a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-239a    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-ethoxy-1-hydroxypentyl)piperidine-1-carboxamide-   I-240a    (3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-241a    (3R)—N—((S)-3-cyclopropyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide-   I-244a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-244b    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-247a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carbothioamide-   I-250a    (3R)-3-((S)-1-(3-chloro-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-251a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-251a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-252a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-253a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-255a    (3R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-256a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-256b    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-257a    (3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-265a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-267a    (3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-270a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-271a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N′-cyano-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamidine-   I-273a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-279a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-280a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)-3-(trans-4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-281a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-282a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-283a    (3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-284a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-286a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-287a    (3R)-3-((S)-1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-288a    (3R)-3-((S)-1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-289a    (3R)-3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-290a    (3R)-3-((S)-1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-291a    (3R)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-293a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-294a    (3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-295a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-295a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-296a    (3R)-3-((R)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-296b    (3R)-3-((1R)-1-(2′-chlorobiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-299a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-301a    (3R)-3-((S)-1-acetamido-1-(3-chlorophenyl)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-302a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-305a    (3R)—N—((S)-1-(2-methoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-306a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-308a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-310a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-(trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide-   I-311a    (3R)-3-((S)-1-(2-(p-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-317a    (3R)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-318a    (3R)-3-((S)-1-(2-(4-fluorophenoxy)-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-319a    (3R)-3-((S)-1-(3,5-difluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-320a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-321a    (3R)-3-((R)-(3-ethoxypropoxy)(3-chloro-2-fluorophenyl)methyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-322a    (3R)-3-((S)-1-(3-chlorophenyl)-5-methoxy-1-(propionamido)pentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-323a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-324a    (3R)-3-((R)-(3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-327a    (3R)—N—((S)-1-(2-ethoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-330a    (3R)-3-((S)-1-(2-(allyloxy)-3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-331a    (3R)—N—((S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-336a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-(propionamido)pentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-340a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-343a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-345a    3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide-   I-346a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-347a    (3R)-3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-350a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-354a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-357a    (3R)-3-((S)-1-(3-cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-359a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-362a    (3R)-3-((S)-4-acetamido-1-(2-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-363a    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-363b    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((R)-1-(3-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-366a    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-hydroxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-367a    (3R)—N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-368a    (3R)—N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-369a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-370a    (3R)—N—((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-370b    (3R)—N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-370c    (3R)—N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((R)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-371a    (3R)—N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-372a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-373a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-374a    (3R)-3-((S)-1-(benzofuran-4-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-375a    (3R)-3-((S)-4-acetamido-1-(3,5-dimethylphenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-377a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-379a    (3R)-3-((S)-1-(2-cyano-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-381a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-2-((R)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxamide-   I-382a    (3R)-3-((S)-4-acetamido-1-(3-fluoro-5-methylphenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-383a    (3R)-3-((S)-4-acetamido-1-(2-fluoro-5-methylphenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-385a    (3R)-3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-386a    (3R)-3-((S)-1-(3-chloro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-388a    (3R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-389a    (3R)-3-((S)-4-acetamido-1-(3,5-difluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-390a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-393b    (3R)-3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-395a    (3R)—N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-398a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-399a    (3R)—N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-400a    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,4-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-401a    (3R)—N—((S)-1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-402b    (3R)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-403a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-403b    (3R)-3-((R)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-404a    (R)-2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-405a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-406a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamide-   I-408a    (3R)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-410a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-411a    (3R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-413a    (3R)-2-((R)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-416a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-propionamidobutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-418a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(3-methylureido)butyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-423a    (3R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-424a    (3R)-3-((S)-4-acetamido-1-(3-chloro-5-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-425a    (3R)-3-((S)-4-acetamido-1-(2-chloro-3-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-428a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-428a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432b    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-433a    (3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-433b    (3R)-3-((R)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-434a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-435a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-Methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-435b    (3R)-3-((R)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-436a    (3R)—N—((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-437a    (3R)-2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-438a    (3R)-3-((S)-1-(3-chlorophenyl)-4-(cyclopropanecarboxamido)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-442a    (3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-447a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cycloheptyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-450a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(sulfamoylamino)butyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-451a    (3R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N—((S)-1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-459a    (3R)-3-((S)-1-(2-bromo-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-464a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(2,2,2-trifluoroacetamido)butyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-469a    (3R)-3-((S)-1-butyramido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-470a    (S)-3-((R)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-472a    (3R)—N—((S)-2-amino-5-methoxy-4,4-dimethylpentyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-474a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-475a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-476a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-476b    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-478a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-fluoro-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-480a    (3R)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-485a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-488a    (3R)—N-((2S,3S)-3-amino-4-cyclohexyl-1-hydroxybutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-490a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-491a    (3R)—N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide-   I-492a    (3R)—N—((S)-2-amino-3-(4,4-difluorocyclohexyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-493a    (3R)—N-((1S,2R)-3-amino-1-(noradamant-3-yl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-497a    (3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-498a    (3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-499a    (3R)—N-((1S,2R)-(3-amino-1-(noradamant-3-yl)-1-hydroxy)propan-2-yl)-3-((S)-1-(2-fluoro-3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-503a    (3R)—N—((S)-2-amino-3-cyclopentylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-514a    (3R)—N-((2S)-1-amino-3-(tetrahydrofuran-2-yl)propan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-520a    (3R)—N—((S)-2-amino-4-cyclohexylbutyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-522a    (S)-3-((R)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-524a    (3R)-3-((R)-(3-chloro-2-fluorophenyl)(3-methoxypropoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-526a    (3R)—N-((2S)-1-amino-3-(tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-531a    (3R)-3-((R)-(3-chlorophenyl)(2-propionamidoethoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-533a    (3R)—N-((3S,4S)-4-cyclohexylpiperidin-3-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-534a    (3R)-3-((1S)-1-(3-chlorophenyl)-1,6-dihydroxyheptyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-536a    (3R)—N-((2S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((R)-(2,3-difluorophenyl)(2-propionamidoethoxy)methyl)piperidine-1-carboxamide-   I-544a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3S,4S)-4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide-   I-545a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-546a    (3R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamide-   I-546b    (3R)-3-((R)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamide-   I-547a    (3R)-3-((R)-(3-chloro-2-fluorophenyl)(2-propionamidoethoxy)methyl)-N-((2S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-549a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3R,4R)-4-(pentan-3-yloxy)piperidin-3-yl)piperidine-1-carboxamide-   I-551a    (3R)—N-((1S,2R)-3-amino-1-(trans-4-fluorocyclohexyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-552a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(3-noradamantyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-554a    (R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-((1r,3R,4S)-3,4-difluorocyclopentyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-556a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-558a    (3R)-3-((S)-1-acetamido-1-(3-chlorophenyl)-5-ethoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-559a    (3R)—N-((2R,3S)-2-amino-3-(3-noradamantyl)-3-hydroxypropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

The following are more preferred compounds of Formula I:

-   I-50a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide-   I-53a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-64a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-151a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-153a    (3R)—N—((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-176a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3,5-dimethylphenyl)pentyl)piperidine-1-carboxamide-   I-180a    (3R)-3-((S)-1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-182a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-183a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-184a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-185a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-190a    (3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-195a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-196a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-197a    (3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide-   I-198a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-202b    (3R)—N-((1S,2R)-3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-206a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-210a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-227a    (3R)-3-((S)-4-(acetylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-239a    (R)—N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-ethoxy-1-hydroxypentyl)piperidine-1-carboxamide-   I-240a    (3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-247a    (3R)-3-(S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carbothioamide-   I-250a    (3R)-3-(S)-1-(3-chloro-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-251a    (R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-251a    (R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-252a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-253a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-256a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-256b    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-265a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-267a    (3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-279a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-280a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)-3-(trans-4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-283a    (3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-284a    (3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-291a    (3R)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide-   I-295a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-295a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-299a    (3R)—N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-302a    (3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-306a    (3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-320a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-354a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-369a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-372a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-373a    (3R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-374a    (3R)-3-((S)-1-(benzofuran-4-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-388a    (3R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-390a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide-   I-393b    (3R)-3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-398a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-399a    (3R)—N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-403a    (3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-403b    (3R)-3-((R)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-404a    (R)-2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-405a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-408a    (3R)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-416a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-propionamidobutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-423a    (3R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-424a    (3R)-3-((S)-4-acetamido-1-(3-chloro-5-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-428a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432b    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-433a    (3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-434a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-435a    (3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-437a    (3R)-2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)morpholine-4-carboxamide-   I-442a    (3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-447a    (R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cycloheptyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-464a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(2,2,2-trifluoroacetamido)butyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-474a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-475a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide-   I-476a    (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-485a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide-   I-492a    (3R)—N—((S)-2-amino-3-(4,4-difluorocyclohexyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide-   I-498a    (3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-531a    (3R)-3-((R)-(3-chlorophenyl)(2-propionamidoethoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-547a    (3R)-3-((R)-(3-chloro-2-fluorophenyl)(2-propionamidoethoxy)methyl)-N-((2S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

The following are highly preferred compounds:

-   I-295a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-423a    (3R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-432a    (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide-   I-531a    (3R)-3-((R)-(3-chlorophenyl)(2-propionamidoethoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Another embodiment of the invention is an intermediate compound ofFormula III

whereinR¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl, heteroaryl, or bicyclicheteroaryl, optionally substituted with 1 or 2 substituentsindependently selected from:1) fluorine, chlorine, bromine, iodine, trifluoromethanesulfonyloxy,cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)-cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)-alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cyclo-alkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, and(C₁-C₆)alkanesulfonyl;or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio,naphthylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy, orheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy, and aminocarbonyl;X and Y is each a single bond;R² is (C₅-C₈)cycloalkylalkyl, halo(C₅-C₈)alkyl,halo(C₅-C₈)cycloalkylalkyl, (C₅-C₈)alkoxy, (C₅-C₈)cycloalkylalkoxy,halo(C₅-C₈)alkoxy, (C₅-C₈)alkylthio, halo(C₅-C₈)alkylthio,hydroxy(C₅-C₈)-alkyl, (C₁-C₃)alkoxy(C₃-C₅)alkyl,(C₁-C₃)alkoxy(C₃-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₃-C₅)alkyl,halo(C₁-C₃)alkoxy(C₃-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₃-C₅)alkyl,(C₁-C₃)alkylthio(C₃-C₅)alkyl, halo(C₁-C₃)alkylthio(C₃-C₅)-alkyl,(C₁-C₃)alkoxy(C₃-C₅)alkoxy, (C₁-C₂)alkm(C₂-C₄)-alkoxy(C₁-C₂)alkyl,hydroxy(C₅-C₈)alkoxy, (C₃-C₆)cycloalkoxy(C₃-C₅)alkoxy,halo(C₁-C₃)alkoxy-(C₃-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₃-C₅)alkoxy,hydroxy(C₅-C₈)alkylthio, (C₁-C₃)alkoxy(C₃-C₅)alkylthio,(C₁-C₃)alkylthio(C₃-C₅)alkoxy, (C₁-C₃)alkylthio(C₃-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₂-C₄)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₂-C₄)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₂-C₄)alkylthio,(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkyl,(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkoxy,(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkylthio,di(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkyl,di(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkoxy,di(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkylthio oraminocarbonyl(C₂-C₄)alkyl;

R³ is H or OH;

provided that when R³ is OH, R² is not (C₅-C₈)alkoxy,(C₅-C₈)cycloalkylalkoxy, halo(C₅-C₈)-alkoxy, (C₅-C₈)alkylthio,halo(C₅-C₈)alkylthio, (C₁-C₃)alkoxy(C₃-C₅)alkoxy, hydroxy(C₅-C₈)alkoxy,(C₃-C₆)cycloalkoxy(C₃-C₅)alkoxy, halo(C₁-C₃)alkoxy(C₃-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₃-C₅)alkoxy, hydroxy(C₅-C₈)alkylthio,(C₁-C₃)alkoxy(C₃-C₅)alkylthio, (C₁-C₃)-alkylthio(C₃-C₅)-alkoxy,(C₁-C₃)alkylthio(C₃-C₅)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₂-C₄)alkoxy,(C₃-C₄)cyclo-alkanecarbonylamino(C₂-C₄)alkylthio,(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkoxy,(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkylthio,di(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkoxy,di(C₁-C₃)alkylaminocarbonylamino(C₂-C₄)alkylthio,

A is 2,4-disubstituted morpholine with R¹XCR²R³Y attached at the2-position and E attached at the 4-position, 1,3-disubstitutedpiperidine with R¹XCR²R³Y attached at the 3-position and E attached atthe 1-position, or 1,3-disubstituted-3-methylpiperidine with R¹XCR²R³Yattached at the 3-position and E attached at the 1-position; andE is hydrogen or an amine protecting group.and the enantiomers, diastereomers and salts thereof.

Amine protecting groups include carbamate, amide, and sulfonamideprotecting groups known in the art (T. W. Greene and P. G. M. Wuts“Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., NewYork 1999).

Another embodiment of the invention is an intermediate compound ofFormula IIIa

wherein:

Z is CH₂ or O

R¹ is a) cyclohexyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl,2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl,7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl,1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionallysubstituted with 1 to 3 substituents independently selected from:fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, t-butyl,isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1-yl,cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio,allyloxy, cyclopropylmethoxy, 2-(cyclopropyl)ethoxy, cyclopentyloxy,cyclopentylmethoxy, benzyloxy, hydroxyl, aminocarbonyl, methoxycarbonyl,phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenylphenoxy, benzyloxy and heteroaryloxy groups are optionally substitutedwith 1 to 3 substituents independently selected from fluorine, chlorine,cyano, methyl, trifluoromethyl, and aminocarbonyl;R² is 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl,4-hydroxypentyl, 4-hydroxyhexyl, 3-ethoxypropyl, 4-methoxybutyl,4-ethoxybutyl, 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,3-propoxypropoxy, or 2-cyclopropylethoxy, 2-(methoxy)ethoxymethyl,3-(acetylamino)propyl, 3-(propionylamino)propyl,3-(butanoylamino)propyl, 3-((2-methoxypropionyl)amino)propyl,3-(cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl,3-(methylaminocarbonylamino)propyl,3-(dimethylaminocarbonylamino)propyl, 2-(acetylamino)ethoxy, or3-(aminosulfonylamino)propyl;

R³ is H or OH;

provided that when R³ is OH, R² is not 2-(ethoxy)ethoxy,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, 2-cyclopropylethoxyor 2-(acetylamino)ethoxy; andE is hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, methanesulfonyl, or2-(trimethylsilyl)ethoxysulfonyl.and the enantiomers, diastereomers and salts thereof.

Another embodiment of the invention is an intermediate compound ofFormula IIIb

wherein:

Z is CH₂ or O

R¹ is a) cyclohexyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl,2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl,7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl,1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionallysubstituted with 1 to 3 substituents independently selected from:fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, t-butyl,isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1-yl,cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio,allyloxy, cyclopropylmethoxy, 2-(cyclopropyl)ethoxy, cyclopentyloxy,cyclopentylmethoxy, benzyloxy, hydroxyl, aminocarbonyl, methoxycarbonyl,phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenylphenoxy, benzyloxy and heteroaryloxy groups are optionally substitutedwith 1 to 3 substituents independently selected from fluorine, chlorine,cyano, methyl, trifluoromethyl, and aminocarbonyl;R² is 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl,4-hydroxypentyl, 4-hydroxyhexyl, 3-ethoxypropyl, 4-methoxybutyl,4-ethoxybutyl, 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,3-propoxypropoxy, or 2-cyclopropylethoxy, 3-(acetylamino)propyl,3-(propionylamino)-propyl, 3-(butanoylamino)propyl,3-((2-methoxypropionyl)amino)propyl,3-(cyclopropane-carbonylamino)propyl, 3-(trifluoroacetylamino)propyl,3-(methylaminocarbonylamino)propyl,3-(dimethylaminocarbonyl-amino)propyl, 2-(acetylamino)ethoxy, or3-(aminosulfonylamino)propyl;

R³ is H or OH;

provided that when R³ is OH, R² is not 2-(ethoxy)ethoxy,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, 2-cyclopropylethoxyor 2-(acetylamino)ethoxy andE is hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, methanesulfonyl, or2-(trimethylsilyl)ethoxysulfonyl.

Intermediates are useful in the preparation of compounds of Formula I.An embodiment of the invention is each of the following intermediatesand their enantiomers, diastereomers, and salts:

-   (R)-3-((R)-(2-cyclopropylethoxy)(phenyl)methyl)piperidine-   (S)-2-((S)-5-methoxy-1-phenylpentyl)morpholine-   (S)-4-methoxy-1-phenyl-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-2-((S)-(3-methoxypropoxy)(phenyl)methyl)morpholine-   (S)-4-cyclopropyl-1-phenyl-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-   (R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-   (R)-3-((R)-(4-methoxybutoxy)(phenyl)methyl)piperidine-   (S)-4-ethoxy-1-phenyl-1-((R)-piperidin-3-yl)butan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(pyridin-2-yl)pentan-1-ol-   (R)-3-((R)-(3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(3-fluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(4-fluorophenyl)methyl)piperidine-   (S)-1-(1H-imidazol-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(thiophen-3-yl)pentan-1-ol-   (R)-1-cyclohexyl-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butane-1,4-diol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(thiazol-2-yl)pentan-1-ol-   3-((R)-(3-methoxypropoxy)((R)-piperidin-3-yl)methyl)benzonitrile-   4-cyclopropyl-1-(3-fluorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(m-tolyl)methyl)piperidine-   (R)-3-((R)-(3-propoxypropoxy)(phenyl)methyl)piperidine-   (R)-5-methoxy-1-((R)-3-methylpiperidin-3-yl)-1-phenylpentan-1-ol-   (S)-5-ethoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-m-tolylpentan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)piperidine-   (S)-1-(2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-(5-methylthiazol-2-yl)-1-((R)-piperidin-3-yl)pentan-1-ol-   4-chloro-2-((R)-(3-methoxypropoxy)((R)-piperidin-3-yl)methyl)pyridine-   (R)-3-((R)-(3-methoxypropoxy)(2,4-difluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   2-((S)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)acetamide-   (S)-4,4,4-trifluoro-1-((R)-piperidin-3-yl)-1-m-tolylbutan-1-ol-   3-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)benzonitrile-   (R)-3-((R)-(3-methoxypropoxy)(2-allylphenyl)methyl)piperidine-   (S)-1-(2,3-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2,5-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3,5-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-ethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-(3-methoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(3-chlorophenyl)-4-cyclopropyl-1-((S)-piperidin-3-yl)butan-1-ol-   N—((S)-4-(2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   (S)-1-(2-fluoro-3-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-fluoro-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluoro-2-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluoro-4-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluoro-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   2-fluoro-6-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)phenol-   (R)-3-((R)-(3-chlorophenyl)(3-ethoxypropoxy)methyl)piperidine-   (S)-1-(2-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(4-chloropyridin-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   (S)-1-(2,3-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2,5-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3,4-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3,5-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-1-(3-chlorophenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol-   (S)-1-(5-chloro-1-methyl-1H-imidazol-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(benzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(1H-indazol-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-isopropylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   4-fluoro-2-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)benzonitrile-   3-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)benzamide-   (S)-1-(3-chlorophenyl)-5-cyclopropyl-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(2-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   N—((S)-4-(3-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   (S)-5-methoxy-1-(3-(methylthio)phenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   (S)-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-   (S)-1-(3-chloro-2-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(2,3-difluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   N—((S)-4-(3,5-difluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   (R)-3-((R)-(2-(cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)piperidine-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(quinolin-8-yl)pentan-1-ol-   N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide-   N-(2-((S)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide-   (R)-3-((R)-(3-chloro-2-fluorophenyl)(3-ethoxypropoxy)methyl)piperidine-   (S)-1-(2-chloro-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chloro-5-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2,3,4-trifluorophenyl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2,3,5-trifluorophenyl)pentan-1-ol-   (S)-5-methoxy-1-(2-methylbenzofuran-7-yl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (1R)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-(morpholin-2-yl)pentan-1-ol-   (S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol-   (S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(benzo[b]thiophen-4-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(benzo[b]thiophen-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-fluorobenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-fluorobenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   methyl    3-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)benzoate-   (R)-1-(benzo[b]thiophen-7-yl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)propionamide-   (R)-3-((R)-biphenyl-2-yl(3-methoxypropoxy)methyl)piperidine-   1-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-3-methylurea-   (R)-3-((R)-(3-methoxypropoxy)(2-bromophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(2-bromophenyl)methyl)piperidine-   N—((S)-4-(2-chloro-3-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   N—((S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   N—((S)-4-(3-chloro-5-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide-   (R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1,5-dimethoxypentyl)piperidine-   1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-(trifluoromethyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-ethoxy-1-((R)-piperidin-3-yl)-1-(2,3,5-trifluorophenyl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trifluoromethyl)phenyl)pentan-1-ol-   (R)-3-((R)-(2,3-dichlorophenyl)(3-ethoxypropoxy)methyl)piperidine-   (S)-1-(2,3-dichlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(cyclopropylmethoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chloro-2,4-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)cyclopropanecarboxamide-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)butyramide-   (S)-1-(2-phenylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   3-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-1,1-dimethylurea-   (S)-1-(3-bromophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)methanesulfonamide-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trifluoromethoxy)phenyl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(3-(trifluoromethoxy)phenyl)pentan-1-ol-   1-(2-(2-cyclopropylethoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(cyclobutylmethoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(cyclopentyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol-   (S)-5-methoxy-1-(2-(2,2-(dimethyl)propoxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(allyloxy)-5-fluorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-4-cyclopropyl-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-3-((R)-(3-methoxypropoxy)(2-phenethylphenyl)methyl)piperidine-   (S)-1-(2-(2-methylphenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(3-methylphenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(4-methylphenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)—N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2-methoxypropanamide-   N—((S)-1-(2,3-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentyl)propionamide-   (S)—N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2-methoxypropanamide-   (S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   3-(1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentyloxy)propan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(pyridin-4-yloxy)phenyl)pentan-1-ol-   (S)-1-(2-(2-fluorophenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(3-fluorophenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(4-fluorophenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-phenyl-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-isobutylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-tert-butylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-bromo-5-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(cyclopentylmethoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2,2,2-trifluoroacetamide-   (S)-1-(2-(m-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(o-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(benzyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(2-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(3-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(4-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluoro-2-phenoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-fluoro-2-phenoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (3R)-tert-butyl    3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate-   (3R)-tert-butyl    3-((S)-1-(2-(4-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate-   (S)-1-(2-phenyl-3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(3,4-difluorophenyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(cyclohexylmethoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(o-tolyloxy)-3-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(p-tolyloxy)-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-(3-methyl-2-(o-tolyloxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   N—((S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentyl)butyramide-   (S)-1-(2-(4-fluoro-2-methylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(5-fluoro-2-methylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(p-tolyloxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-fluoro-3-(o-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluoro-2-(o-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   1-(2-(4-fluorobenzyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(2-chlorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-chloro-2-phenoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol.-   (S)-1-(3,5-difluoro-2-phenoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-fluoro-2-(4-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trimethylsilyl)benzo[b]thiophen-7-yl)pentan-1-ol-   (S)-1-(3′-chloro-6-fluorobiphenyl-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(allyloxy)-3-bromophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(o-tolyloxy)-3,5-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    and-   (S)-1-(3-chlorophenyl)-2-(2-methoxyethoxy)-1-((R)-piperidin-3-yl)ethanol

When any variable (e.g., aryl, heterocyclyl, R₁, R₂, etc.) occurs morethan once in a compound, its definition on each occurrence isindependent of any other occurrence.

“Alkyl” means a saturated aliphatic branched or straight-chain mono- ordi-valent hydrocarbon radical having the specified number of carbonatoms. Thus, “(C₁-C₈)alkyl” means a radical having from 1-8 carbon atomsin a linear or branched arrangement. “(C₁-C₆)alkyl” includes methyl,ethyl, propyl, butyl, pentyl, and hexyl.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radicalhaving the specified number of carbon atoms. Thus, (C₃-C₇)cycloalkylmeans a radical having from 3-8 carbon atoms arranged in a ring.(C₃-C₇)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groupswhere the halogens are independently selected from fluorine, chlorine,and bromine

Saturated heterocyclic rings are 4-, 5-, 6-, and 7-membered heterocyclicrings containing 1 to 4 heteroatoms independently selected from N, O,and S, and include pyrrolidine, piperidine, tetrahydrofuran,tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran,isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane,1,3-dithiane, 1,4-dithiane, morpholine, thiomorpholine, thiomorpholine1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, and isothiazolidine1,1-dioxide. Oxo substituted saturated heterocyclic rings includetetrahydrothiophene 1-oxide, tetrahydrothiophene 1,1-dioxide,thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,tetrahydro-2H-1,2-thiazine 1,1-dioxide, and isothiazolidine 1,1-dioxide,pyrrolidin-2-one, piperidin-2-one, piperazin-2-one, and morpholin-2-one.

“Heteroaryl” means a monovalent heteroaromatic monocyclic and polycylicring radical containing 1 to 4 heteroatoms independently selected fromN, O, and S. Heteroaryl rings include furyl, thienyl, thiophenyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl,pyridinyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl,benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl,1,2,5-thiadiazolyl, 1,2,5-thiadiazolyl-1-oxide,1,2,5-thiadiazolyl-1,1-dioxide, 1,3,4-thiadiazolyl, 1,2,4-triazinyl,1,3,5-triazinyl, tetrazolyl, and pteridinyl.

Bicyclic heteroaryl rings are bicyclo[4.4.0] and bicyclo[4,3.0] fusedring systems of which at least one ring is aromatic containing 1 to 4heteroatoms independently selected from N, O, and S, and include indole,quinoline, isoquinoline, quinazoline, benzothiophene, benzofuran,2,3-dihydrobenzofuran, benzodioxole, benzimidazole, indazole,benzisoxazole, benzoxazole, and benzothiazole.

Bicycloalkyl rings are fused, bridged and spiro ring systems and includebicyclo[1.1.0]butane, bicyclo[1.2.0]pentane, bicyclo[2.2.0]hexane,bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.2.0]octane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[3.3.2]decane andbicyclo[3.3.3]undecane, spiro[2.2]pentane, spiro[2.3]hexane,spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane andspiro[2.5]octane.

Tricycloalkyl rings are fused, bridged and spiro ring systems andinclude tricyclo[3.3.1.0^(3,7)]nonane (noradamantane) andtricyclo[3.3.1.1^(3,7)]decane (adamantane).

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(C₁-C₄)-alkoxy” includes the methoxy, ethoxy, propoxy, and butoxy.

“Aromatic” means an unsaturated cycloalkyl ring system.

“Aryl” means an aromatic monocyclic or polycyclic ring system. Arylsystems include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, andanthracenyl.

“Hetero” refers to the replacement of at least one carbon atom member ina ring system with at least one heteroatom selected from N, S, and O. Ahetero ring may have 1, 2, 3, or 4 carbon atom members replaced by aheteroatom.

“Oxo” refers to ═O. When an oxo group is a substituent on a carbon atom,they form a carbonyl group (—C(O)—). When one oxo group is a substituenton a sulfur atom, they form a sulfinyl (sulfoxide —S(O)—) group. Whentwo oxo groups are a substituent on a sulfur atom, they form a sulfonyl(sulfone —S(O)₂—) group.

In certain instances herein when describing functional groups, “alkane”,“'cycloalkane” and the like are used interchangeably with “alkyl” and“cycloalkyl”, respectively. Thus, by way of example, “alkanesulfonyl”means an alkyl group attached to a sulfonyl moiety, and“cycloalkanesulfonyl” refers to a cycloalkyl group attached to asulfonyl moiety.

Enantiomers, Diastereomers, and Salts

Certain compounds of Formula I may exist in various stereoisomeric ortautomeric forms. The invention encompasses all such forms, includingactive compounds in the form of essentially pure enantiomers, racemicmixtures, and tautomers.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate, and triethiodide salts.

The compounds of the invention include pharmaceutically acceptableanionic salt forms, wherein the anionic salts include the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate, and triethiodide salts.

The anionic salt form of a compound of the invention includes theacetate, bromide, camsylate, chloride, edisylate, fumarate,hydrobromide, hydrochloride, iodide, isethionate, lactate, mesylate,maleate, napsylate, salicylate, sulfate, and tosylate salts.

It may be necessary and/or desirable during synthesis to protectsensitive or reactive groups on any of the molecules concerned.Representative conventional protecting groups are described in T. W.Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” JohnWiley & Sons, Inc., New York 1999. Protecting groups may be added andremoved using methods well known in the art.

The invention also includes various isomers and mixtures thereof.“Isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers).

Stereoisomers are compounds which differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. The symbol“*” in a structural formula represents the presence of a chiral carboncenter. “R” and “S” represent the configuration of substituents aroundone or more chiral carbon atoms. Thus, “R*” and “S*” denote the relativeconfigurations of substituents around one or more chiral carbon atoms.When a chiral center is not defined as R or S, a mixture of bothconfigurations is present.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration.

Atoms (other than H) attached to a carbocyclic ring may be in a cis ortrans configuration. In the “cis” configuration, the substituents are onthe same side in relationship to the plane of the ring; in the “trans”configuration, the substituents are on opposite sides in relationship tothe plane of the ring. A mixture of “cis” and “trans” species isdesignated “cis/trans”.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

Biological Assay Procedures

The compounds of the invention have enzyme-inhibiting properties. Inparticular, they inhibit the action of the natural enzyme renin. Thelatter passes from the kidneys into the blood where it effects thecleavage of angiotensinogen, releasing the decapeptide angiotensin Iwhich is then cleaved in the blood, lungs, the kidneys and other organsby angiotensin converting enzyme to form the octapeptide angiotensin II.The octapeptide increases blood pressure both directly by binding to itsreceptor, causing arterial vasoconstriction, and indirectly byliberating from the adrenal glands the sodium-ion-retaining hormonealdosterone, accompanied by an increase in extracellular fluid volume.That increase can be attributed to the action of angiotensin II.Inhibitors of the enzymatic activity of renin bring about a reduction inthe formation of angiotensin I. As a result a smaller amount ofangiotensin II is produced. The reduced concentration of that activepeptide hormone is the direct cause of the hypotensive effect of renininhibitors.

The action of renin inhibitors in vitro is demonstrated experimentallyby means of a test which measures the increase in fluorescence of aninternally quenched peptide substrate. The sequence of this peptidecorresponds to the sequence of human angiotensinogen. The following testprotocol is used. All reactions are carried out in a flat bottom whiteopaque microtiter plate. A 4 μL aliquot of 400 μM renin substrate(DABCYL-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS) in 192 μLassay buffer (50 mM BES, 150 mM NaCl, 0.25 mg/mL bovine serum albumin,pH7.0) is added to 4 μL of test compound in DMSO at variousconcentrations ranging from 10 μM to 1 nM final concentrations. Next,100 μL of trypsin-activated recombinant human renin (final enzymeconcentration of 0.2-2 nM) in assay buffer is added, and the solution ismixed by pipetting. The increase in fluorescence at 495 nm (excitationat 340 nm) is measured for 60-360 minutes at rt using a Perkin-ElmerFusion microplate reader. The slope of a linear portion of the plot offluorescence increase as a function of time is then determined, and therate is used for calculating percent inhibition in relation touninhibited control. The percent inhibition values are plotted as afunction of inhibitor concentration, and the IC₅₀ is determined from afit of this data to a four parameter equation. The IC₅₀ is defined asthe concentration of a particular inhibitor that reduces the formationof product by 50% relative to a control sample containing no inhibitor.In the in vitro systems the compounds of the invention exhibitinhibiting activities at minimum concentrations of from approximately5×10⁻⁵ M to approximately 10⁻¹² M. Preferred compounds of the inventionexhibit inhibiting activities at minimum concentrations of fromapproximately 10⁻⁷ M to approximately 10⁻¹² M. (Wang G. T. et al. Anal.Biochem. 1993, 210, 351; Nakamura, N. et al. J. Biochem. (Tokyo) 1991,109, 741; Murakami, K. et al. Anal Biochem. 1981, 110, 232).

The action of renin inhibitors in vitro in human plasma is demonstratedexperimentally by the decrease in plasma renin activity (PRA) levelsobserved in the presence of the compounds. Incubations mixturescontained in the final volume of 250 μL 95.5 mMN,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, pH 7.0, 8 mM EDTA,0.1 mM neomycin sulfate, 1 mg/mL sodium azide, 1 mMphenylmethanesulfonyl fluoride, 2% DMSO and 87.3% of pooled mixed-genderhuman plasma stabilized with EDTA. For plasma batches with low PRA (lessthan 1 ng/ml/hr) ˜2 pM of recombinant human renin was added to achievePRA of 3-4 ng/ml/hr. The cleavage of endogenous angiotensinogen inplasma was carried out at 37° C. for 90 min and the product angiotensinI was measured by competitive radioimmunoassay using DiaSorin PRA kit.Uninhibited incubations containing 2% DMSO and fully inhibited controlswith 2 μM of isovaleryl-Phe-Nle-Sta-Ala-Sta-OH were used for derivingpercent of inhibition for each concentration of inhibitors and fittingdose-response data into a four parametric model from which IC₅₀ values,defined as concentrations of inhibitors at which 50% inhibition occurs,were determined.

The cardiac and systemic hemodynamic efficacy of selective renininhibitors were evaluated in vivo in sodium-depleted, normotensivecynomolgus monkeys and in sodium-depleted, normotensive beagle dogsfollowing a single oral and intravenous administration of the testcompound. Arterial blood pressure was monitored by telemetry in freelymoving, conscious animals.

Cynomolgus Monkey: Six male naïve cynomolgus monkeys weighing between2.5 and 3.5 kg were used in the studies. At least 4 weeks before theexperiment, the monkeys were anesthetized with ketamine hydrochloride(15 mg/kg, i.m.) and xylazine hydrochloride (0.7 mg/kg, i.m.), and wereimplanted into the abdominal cavity with a transmitter (Model#TL11M2-D70-PCT, Data Sciences, St. Paul, Minn.). The pressure catheterwas inserted into the lower abdominal aorta via the femoral artery. Thebipotential leads were placed in Lead II configuration. The animals werehoused under constant temperature (19-25° C.), humidity (>40%) andlighting conditions (12 h light and dark cycle), were fed once daily,and were allowed free access to water. The animals were sodium depletedby placing them on a low sodium diet (0.026%, Expanded. Primate Diet829552 MP-VENaCI (P), Special Diet Services, Ltd., UK) 7 days before theexperiment and furosemide (3 mg/kg, intramuscularly i.m., AventisPharmaceuticals) was administered at −40 h and −16 h prior toadministration of test compound.

For oral dosing, the renin inhibitors were formulated in 0.5%methylcellulose at dose levels of 10 and 30 mg/kg (5 mL/kg) by infantfeeding tubes. For intravenous delivery, a silastic catheter wasimplanted into posterior vena cava via a femoral vein. The catheter wasattached to the delivery pump via a tether system and a swivel joint.Test compound (dose levels of 0.1 to 10 mg/kg, formulated at 5%dextrose) was administered by continuous infusion (1.67 mL:/kg/h) or bybolus injection (3.33 mL/kg in 2 min).

Arterial blood pressures (systolic, diastolic and mean) and bodytemperature were recorded continuously at 500 Hz and 50 Hz,respectively, using the Dataquest™ A.R.T. (Advanced Research Technology)software. Heart rate was derived from the phasic blood pressure tracing.During the recording period, the monkeys were kept in a separate roomwithout human presence to avoid pressure changes secondary to stress.All data were expressed as mean±SEM. Effects of the renin inhibitors onblood pressure were assessed by ANOVA, taking into account the factorsdose and time compared with the vehicle group.

Beagle Dogs: Non-naive Beagle dogs (2 per sex) weighing between 9 and 11kg were used in the studies. Each animal was implanted subcutaneouslywith a telemetry transmitter (Data Sciences) and the blood pressurecatheter was inserted into the left femoral artery. Theelectrocardiogram leads were also tunneled subcutaneously to theappropriate anatomical regions. The animals were housed under constanttemperature and lighting conditions, were fed once daily, and wereallowed free access to water. A sodium depleted state was produced byplacing them on a low-sodium diet (<4 meq/day, a combination of cannedPrescription Diet canine h/d, from Hill's Pet Products and dry pelletsfrom Bio-Serv Inc., Frenchtown, N.J.) beginning 10 days before theexperiment, and furosemide (3 mg/kg i.m.; Aventis Pharmaceuticals) wasadministered at −40 and −16 h prior to administration of test compound.

A renin inhibitor was orally administered by orogastric gavage to allovernight fasted anaimals at a dose level of 30 mg/kg (4 mL/kgformulated in 0.5% methylcellulose). Food was given 4 h postdose. Insome experiments, the renin inhibitor was administered by bolus i.v. atincreasing dose levels of 1, 3 and 6 mg/kg (2, 6 and 20 mg/mL formulatedin sterile saline). Cardiovascular parameters were collectedcontinuously at least 80 min predose and 3 h postdose, followed by every10 min for 5 h and every 30 min for 16 h postdose. The Dataquest™ ART(version 2.2) software package from DSI (Data Sciences International)was used to collect telemetered cardiovascular data.

The efficacy of the renin inhibitors was also evaluated in vivo indouble transgenic rats engineered to express human renin and humanangiotensinogen (Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz R,Menard J, Murakami K, Luft F C, Ganten D. High human renin hypertensionin transgenic rats. Hypertension 1997, 29, 428-434).

Experiments were conducted in 6-week-old double transgenic rats (dTGRs).The model has been described in detail earlier. Briefly, the human reninconstruct used to generate transgenic animals made up the entire genomichuman renin gene (10 exons and 9 introns), with 3.0 kB of the5′-promoter region and 1.2 kB of 3′ additional sequences. The humanangiotensinogen construct made up the entire human angiotensinogen gene(5 exons and 4 introns), with 1.3 kB of 5′-flanking and 2.4 kB of3′-flanking sequences. The rats were purchased from RCC Ltd(Füllinsdorf, Switzerland). Radio telemetry transmitters were surgicallyimplanted at 4 weeks of age. The telemetry system provided 24-hrecordings of systolic, mean, diastolic arterial pressure (SAP, MAP,DAP, respectively) and heart rate (HR). Beginning on day 42, animalswere transferred to telemetry cages. A 24 h telemetry reading wasobtained. Rats were then dosed orally on the following 4 consecutivedays (days 43-46). The rats were monitored continuously and allowed freeaccess to standard 0.3%-sodium rat chow and drinking water.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the levels of asparticprotease products is effective in treating the disease state or intreating infections in which the infectious agent depends upon theactivity of an aspartic protease. In hypertension elevated levels ofangiotensin I, the product of renin catalyzed cleavage of angioteninogenare present. Elevated levels of β amyloid, the product of BACE activityon amyloid precursor protein, are believed to be responsible for theamyloid plaques present in the brains of Alzheimer's disease patients.The viruses HIV and HTLV depend on their respective aspartic proteasesfor viral maturation. Plasmodium falciparum uses plasmepsins I and II todegrade hemoglobin.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the levels of renin productsis effective in treating a disease state. In hypertension elevatedlevels of angiotensin I, the product of renin catalyzed cleavage ofangioteninogen are present. Thus, the compounds of the invention can beused in the treatment of hypertension, congestive heart failure, cardiachypertrophy, cardiac fibrosis, cardiomyopathy post-infarction,complications resulting from diabetes, such as nephropathy, vasculopathyand neuropathy, diseases of the coronary vessels, proteinuria,albumenuria, post-surgical hypertension, metabolic syndrome, obesity,restenosis following angioplasty, raised intra-ocular pressure,glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety states,and cognitive disorders (Fisher N. D.; Hollenberg N. K. Expert Opin.Investig. Drugs. 2001, 10, 417-26).

A pharmaceutical composition of the invention may, alternatively or inaddition to a compound of Formula I, comprise a pharmaceuticallyacceptable salt of a compound of Formula I or a prodrug orpharmaceutically active metabolite of such a compound or salt and one ormore pharmaceutically acceptable carriers therefor.

The compositions of the invention are aspartic protease inhibitors. Saidcompositions contain compounds having a mean inhibition constant (IC₅₀)against aspartic proteases of between about 5,000 nM to about 0.001 nM;preferably between about 50 nM to about 0.001 nM; and more preferablybetween about 5 nM to about 0.01 nM.

The compositions of the invention reduce blood pressure. Compounds I-1through I-559 have an IC₅₀ for renin of between about 5,000 nM to about0.001 nM. Many of these compounds have an IC₅₀ between about 50 nM toabout 0.001 nM; and others between about 5 nM to about 0.001 nM.

The invention includes a therapeutic method for treating or amelioratingan aspartic protease mediated disorder in a subject in need thereofcomprising administering to a subject in need thereof an effectiveamount of a compound of Formula I, or the enantiomers, diastereomers, orsalts thereof or composition thereof.

Administration methods include administering an effective amount (i.e.,a therapeutically effective amount) of a compound or composition of theinvention at different times during the course of therapy orconcurrently in a combination form. The methods of the invention includeall known therapeutic treatment regimens.

“Prodrug” means a pharmaceutically acceptable form of an effectivederivative of a compound (or a salt thereof) of the invention, whereinthe prodrug may be: 1) a relatively active precursor which converts invivo to a compound of the invention; 2) a relatively inactive precursorwhich converts in vivo to a compound of the invention; or 3) arelatively less active component of the compound that contributes totherapeutic activity after becoming available in vivo (i.e., as ametabolite). See “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

“Metabolite” means a pharmaceutically acceptable form of a metabolicderivative of a compound (or a salt thereof) of the invention, whereinthe derivative is an active compound that contributes to therapeuticactivity after becoming available in vivo.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. Such responseincludes alleviation of the symptoms of the disease or disorder beingtreated. The effective amount of a compound of the invention in such atherapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day.

The invention includes the use of a compound of the invention for thepreparation of a composition for treating or ameliorating an asparticprotease mediated chronic disorder or disease or infection in a subjectin need thereof, wherein the composition comprises a mixture one or morecompounds of the invention and an optional pharmaceutically acceptablecarrier.

“Pharmaceutically acceptable carrier” means compounds and compositionsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention and that, when appropriately administeredto an animal or human, do not produce an adverse reaction.

“Aspartic protease mediated disorder or disease” includes disorders ordiseases associated with the elevated expression or overexpression ofaspartic proteases and conditions that accompany such diseases.

An embodiment of the invention includes administering a renin inhibitingcompound of Formula I or composition thereof in a combination therapy(see U.S. Pat. No. 5,821,232, U.S. Pat. No. 6,716,875, U.S. Pat. No.5,663,188, or Fossa, A. A.; DePasquale, M. J.; Ringer, L. J.; Winslow,R. L. “Synergistic effect on reduction in blood pressure withcoadministration of a renin inhibitor or an angiotensin-convertingenzyme inhibitor with an angiotensin II receptor antagonist” DrugDevelopment Research 1994, 33(4), 422-8) with one or more additionalagents for the treatment of hypertension including α-blockers,β-blockers, calcium channel blockers, diuretics, natriuretics,saluretics, centrally acting antiphypertensives, angiotensin convertingenzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP)inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthaseinhibitors, aldosterone-receptor antagonists, or endothelin receptorantagonists.

α-Blockers include doxazosin, prazosin, tamsulosin, and terazosin.

β-Blockers for combination therapy are selected from atenolol, bisoprol,metoprolol, acetutolol, esmolol, celiprolol, taliprolol, acebutolol,oxprenolol, pindolol, propanolol, bupranolol, penbutolol, mepindolol,carteolol, nadolol, carvedilol, and their pharmaceutically acceptablesalts.

Calcium channel blockers include dihydropyridines (DHPs) and non-DHPs.The preferred DHPs are amlodipine, felodipine, ryosidine, isradipine,lacidipine, nicardipine, nifedipine, nigulpidine, niludipine,nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and theirpharmaceutically acceptable salts. Non-DHPs are flunarizine,prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil,tiapamil, and verampimil, and their pharmaceutically acceptable salts.

A diuretic is, for example, a thiazide derivative selected fromamiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide,and chlorothalidon.

Centrally acting antiphypertensives include clonidine, guanabenz,guanfacine and methyldopa.

ACE inhibitors include alacepril, benazepril, benazaprilat, captopril,ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril,lisinopril, moexipiril, moveltopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril,and zofenopril. Preferred ACE inhibitors are benazepril, enalpril,lisinopril, and ramipril.

Dual ACE/NEP inhibitors are, for example, omapatrilat, fasidotril, andfasidotrilat.

Preferred ARBs include candesartan, eprosartan, irbesartan, losartan,olmesartan, tasosartan, telmisartan, and valsartan.

Preferred aldosterone synthase inhibitors are anastrozole, fadrozole,and exemestane.

Preferred aldosterone-receptor antagonists are spironolactone andeplerenone.

A preferred endothelin antagonist is, for example, bosentan, enrasentan,atrasentan, darusentan, sitaxsentan, and tezosentan, and theirpharmaceutically acceptable salts.

An embodiment of the invention includes administering an HIV proteaseinhibiting compound of Formula I or composition thereof in a combinationtherapy with one or more additional agents for the treatment of AIDSincluding reverse transcriptase inhibitors, non-nucleoside reversetranscriptase inhibitors, other HIV protease inhibitors, HIV integraseinhibitors, attachment and fusion inhibitors, antisense drugs, andimmune stimulators.

Preferred reverse transcriptase inhibitors are zidovudine, didanosine,zalcitabine, stavudine, lamivudine, abacavir, tenofovir, andemtricitabine.

Preferred non-nucleoside reverse transcriptase inhibitors arenevirapine, delaviridine, and efavirenz.

Preferred HIV protease inhibitors are saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, lopinavir, atazanavir, and fosamprenavir.

Preferred HIV integrase inhibitors are L-870,810 and S-1360.

A preferred attachment and fusion inhibitor is enfuvirtide.

An embodiment of the invention includes administering β-secretaseinhibiting compound of Formula I or composition thereof in a combinationtherapy with one or more additional agents for the treatment ofAlzheimer's disease including tacrine, donepezil, rivastigmine,galantamine, and memantine.

An embodiment of the invention includes administering a plasmepsininhibiting compound of Formula I or composition thereof in a combinationtherapy with one or more additional agents for the treatment of malariaincluding artemisinin, chloroquine, halofantrine, hydroxychloroquine,mefloquine, primaquine, pyrimethamine, quinine, and sulfadoxine

Combination therapy includes co-administration of the compound of theinvention and said other agent, sequential administration of thecompound and the other agent, administration of a composition containingthe compound and the other agent, or simultaneous administration ofseparate compositions containing the compound and the other agent.

The invention further includes the process for making the compositioncomprising mixing one or more of the present compounds and an optionalpharmaceutically acceptable carrier; and includes those compositionsresulting from such a process, which process includes conventionalpharmaceutical techniques.

The compositions of the invention include ocular, oral, nasal,transdermal, topical with or without occlusion, intravenous (both bolusand infusion), and injection (intraperitoneally, subcutaneously,intramuscularly, intratumorally, or parenterally). The composition maybe in a dosage unit such as a tablet, pill, capsule, powder, granule,liposome, ion exchange resin, sterile ocular solution, or oculardelivery device (such as a contact lens and the like facilitatingimmediate release, timed release, or sustained release), parenteralsolution or suspension, metered aerosol or liquid spray, drop, ampoule,auto-injector device, or suppository; for administration ocularly,orally, intranasally, sublingually, parenterally, or rectally, or byinhalation or insufflation.

Compositions of the invention suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release, and sustained release formulations),granule's and powders; and, liquid forms such as solutions, syrups,elixirs, emulsions, and suspensions. Forms useful for ocularadministration include sterile solutions or ocular delivery devices.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

The compositions of the invention may be administered in a form suitablefor once-weekly or once-monthly administration. For example, aninsoluble salt of the active compound may be adapted to provide a depotpreparation for intramuscular injection (e.g., a decanoate salt) or toprovide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains atherapeutically effective amount of the active ingredient necessary toprovide a therapeutic effect. The composition may contain from about5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5mg) of a compound of the invention or salt form thereof and may beconstituted into any form suitable for the selected mode ofadministration. The composition may be administered about 1 to about 5times per day. Daily administration or post-periodic dosing may beemployed.

For oral administration, the composition is preferably in the form of atablet or capsule containing, e.g., 500 to 0.5 milligrams of the activecompound. Dosages will vary depending on factors associated with theparticular patient being treated (e.g., age, weight, diet, and time ofadministration), the severity of the condition being treated, thecompound being employed, the mode of administration, and the strength ofthe preparation.

The oral composition is preferably formulated as a homogeneouscomposition, wherein the active ingredient is dispersed evenlythroughout the mixture, which may be readily subdivided into dosageunits containing equal amounts of a compound of the invention.Preferably, the compositions are prepared by mixing a compound of theinvention (or pharmaceutically acceptable salt thereof) with one or moreoptionally present pharmaceutical carriers (such as a starch, sugar,diluent, granulating agent, lubricant, glidant, binding agent, anddisintegrating agent), one or more optionally present inertpharmaceutical excipients (such as water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, and syrup), one ormore optionally present conventional tableting ingredients (such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate, and any of a variety of gums), and anoptional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose andbeta-lactose), corn sweeteners and natural and synthetic gums (e.g.,acacia and tragacanth). Disintegrating agents include starch, methylcellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form.Tablets may be sugarcoated or filmcoated using standard techniques.Tablets may also be coated or otherwise compounded to provide aprolonged, control-release therapeutic effect. The dosage form maycomprise an inner dosage and an outer dosage component, wherein theouter component is in the form of an envelope over the inner component.The two components may further be separated by a layer which resistsdisintegration in the stomach (such as an enteric layer) and permits theinner component to pass intact into the duodenum or a layer which delaysor sustains release. A variety of enteric and non-enteric layer orcoating materials (such as polymeric acids, shellacs, acetyl alcohol,and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow releasecomposition; wherein the composition includes a compound of theinvention and a biodegradable slow release carrier (e.g., a polymericcarrier) or a pharmaceutically acceptable non-biodegradable slow releasecarrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well knownin the art. Biodegradable carriers are used to form particles ormatrices which retain an active agent(s) and which slowlydegrade/dissolve in a suitable environment (e.g., aqueous, acidic, basicand the like) to release the agent. Such particles degrade/dissolve inbody fluids to release the active compound(s) therein. The particles arepreferably nanoparticles (e.g., in the range of about 1 to 500 nm indiameter, preferably about 50-200 nm in diameter, and most preferablyabout 100 nm in diameter). In a process for preparing a slow releasecomposition, a slow release carrier and a compound of the invention arefirst dissolved or dispersed in an organic solvent. The resultingmixture is added into an aqueous solution containing an optionalsurface-active agent(s) to produce an emulsion. The organic solvent isthen evaporated from the emulsion to provide a colloidal suspension ofparticles containing the slow release carrier and the compound of theinvention.

The compound of Formula I may be incorporated for administration orallyor by injection in a liquid form such as aqueous solutions, suitablyflavored syrups, aqueous or oil suspensions, flavored emulsions withedible oils such as cottonseed oil, sesame oil, coconut oil or peanutoil and the like, or in elixirs or similar pharmaceutical vehicles.Suitable dispersing or suspending agents for aqueous suspensions,include synthetic and natural gums such as tragacanth, acacia, alginate,dextran, sodium carboxymethylcellulose, methylcellulose,polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitablyflavored suspending or dispersing agents may also include synthetic andnatural gums. For parenteral administration, sterile suspensions andsolutions are desired. Isotonic preparations, which generally containsuitable preservatives, are employed when intravenous administration isdesired.

The compounds may be administered parenterally via injection. Aparenteral formulation may consist of the active ingredient dissolved inor mixed with an appropriate inert liquid carrier. Acceptable liquidcarriers usually comprise aqueous solvents and other optionalingredients for aiding solubility or preservation. Such aqueous solventsinclude sterile water, Ringer's solution, or an isotonic aqueous salinesolution. Other optional ingredients include vegetable oils (such aspeanut oil, cottonseed oil, and sesame oil), and organic solvents (suchas solketal, glycerol, and formyl). A sterile, non-volatile oil may beemployed as a solvent or suspending agent. The parenteral formulation isprepared by dissolving or suspending the active ingredient in the liquidcarrier whereby the final dosage unit contains from 0.005 to 10% byweight of the active ingredient. Other additives include preservatives,isotonizers, solubilizers, stabilizers, and pain-soothing agents.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using asuitable intranasal vehicle.

Compounds of the invention may also be administered topically using asuitable topical transdermal vehicle or a transdermal patch.

For ocular administration, the composition is preferably in the form ofan ophthalmic composition. The ophthalmic compositions are preferablyformulated as eye-drop formulations and filled in appropriate containersto facilitate administration to the eye, for example a dropper fittedwith a suitable pipette. Preferably, the compositions are sterile andaqueous based, using purified water. In addition to the compound of theinvention, an ophthalmic composition may contain one or more of: a) asurfactant such as a polyoxyethylene fatty acid ester; b) a thickeningagents such as cellulose, cellulose derivatives, carboxyvinyl polymers,polyvinyl polymers, and polyvinylpyrrolidones, typically at aconcentration n the range of about 0.05 to about 5.0% (wt/vol); c) (asan alternative to or in addition to storing the composition in acontainer containing nitrogen and optionally including a free oxygenabsorber such as Fe), an anti-oxidant such as butylated hydroxyanisol,ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at aconcentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at aconcentration of about 0.01 to 0.5% (wt/vol); and e) other excipientssuch as an isotonic agent, buffer, preservative, and/or pH-controllingagent. The pH of the ophthalmic composition is desirably within therange of 4 to 8.

Methods of Preparation

In the discussion below R¹, R², R³, X, Y, A, Q, R⁴, L, R⁵, R⁶, R⁷, R⁸,L, G, R⁹, and R¹⁰ are defined as described above for compounds ofFormula I and E is defined as describe above for compounds of FormulaIII. In cases where the synthetic intermediates and final products ofFormula I described below contain potentially reactive functionalgroups, for example amino, hydroxyl, thiol and carboxylic acid groups,that may interfere with the desired reaction, it may be advantageous toemploy protected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. (T. W. Greene and P. G. M. Wuts “ProtectiveGroups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999).

A compound of Formula I is prepared by reaction of an intermediate ofFormula IV with an amine intermediate of formula V:

wherein Z¹ in IV is a leaving group such as halide, alkanesulfonate,haloalkanesulfonate, arylsulfonate, aryloxide, heteroaryloxide, azole,azolium salt, or alkoxide.

Alternatively, a compound of Formula I is prepared by reaction of acompound of formula VI with a compound of formula VII wherein Z¹ is aleaving group such as halide, alkanesulfonate, arylsulfonate, aryloxide,azole, azolium salt, or alkoxide:

wherein the H atom in VI is attached to a nitrogen atom that is part ofA.

Furthermore, compounds of Formula I can also be prepared from othercompounds of Formula I and protected compounds of Formula I:

For example, when a bromophenyl, iodophenyl ortrifluoromethanesulfonyloxyphenyl group is present in a compound ofFormula I, it may be transformed into a biphenyl using a Suzukicoupling, to an alkynylbenzene using a Sonogashira coupling, to anallylbenzene using a Stille coupling, to a cyanobenzene using CuCN or toa methoxycarbonylbenzene using a palladium catalyzed carbonylation inthe presence of methanol. Another example is the transformation of acompound of Formula I wherein R³═OH to the analogous compound whereinR³═H by dehydration followed by hydrogenation or in a single step bydeoxygenation using Raney nickel. Another example is the deoxygenationof a compound of Formula I wherein Q=Q11 to a compound of Formula Iwhere Q=Q10. Another example is the reaction of a compound of Formula Iwherein R²═OH and R³═H with an alcohol in the presence of acid to afforda compound of Formula I wherein R² is a group attached through an etherlinkage.

Intermediates of Formula IV wherein Z¹=chlorine and Q is Q1, Q6 or Q8that is attached to a carbon atom that is part of A are prepared fromintermediates VIII:

by reaction with, for example, thionyl chloride or oxalyl chloride.

Intermediates of Formula IV wherein Q is Q9 or Q11 or Q12, Q is attachedto a nitrogen atom that is part of A and Z¹ is methoxy are prepared fromintermediates VI by reaction with 3,4-dimethoxy-3-cyclobutene-1,2-dione,3,4-dimethoxy-1,2,5-thiadiazole-1-oxide and3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide respectively:

Intermediates of Formula IV wherein Q is Q1, Q1 is attached to anitrogen atom that is part of A and Z¹ is chlorine, 1-imidazolyl, orp-nitrophenoxy are prepared from intermediates of formula VI wherein His attached to a nitrogen atom that is part of A by reaction withphosgene, 1,1′-carbonyldiimidazole, or p-nitrophenyl chloroformaterespectively.

Intermediates of formula VI wherein H is attached to a nitrogen atomthat is part of A are prepared from intermediates of Formula IX:

wherein E is an amine protecting group, including carbamate, amide, andsulfonamide protecting groups known in the art (T. W. Greene and P. G.M. Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons,Inc., New York 1999).

Intermediates of Formula IX wherein R³═OH are prepared fromintermediates of formula X by addition of an organometallic reagent offormula R²M where M is for example Li, MgCl, MgBr, or Mgl to thecarbonyl group of X:

Intermediates of Formula IX wherein R³═H and A² is a group attached byan ether linkage are prepared from intermediates of formula XI byreaction with an alkylating agent under basic conditions or by reactionwith an alcohol of formula R²OH under acidic conditions.

Intermediates of formula XI are prepared by reduction of intermediatesof formula X:

or by addition of an organometallic reagent of formula XII wherein M is,for example Li, MgCl, MgBr, or MgI to an aldehyde of Formula XIII:

Intermediates of formula X are prepared by the addition of anorganometallic reagent of formula XII to a carboxylic acid derivative offormula XIV wherein Z² is an alkoxide, dialkylamino group, or analkoxyalkylamino group:

Organometallic reagents of formula XII are prepared by known processincluding halogen-lithium exchange, ortho-lithiation and treatment ofhalides R¹X-Hal with magnesium or lithium metal.

Intermediates of formula X are also prepared by oxidation of anintermediate of formula XI:

Optionally protected compounds of Formula I are prepared from compoundsof formula XV by addition of an organometallic R²M:

Intermediates of formula XV wherein Q is Q1 and Q1 is attached to acarbon atom that is part of A are prepared by coupling of intermediatesof formula XVI and amine intermediates of formula V using peptideforming reagents or by activating XVI as an acid chloride.

Intermediates of formula XVI in which Q=Q1, Q3, Q6, Q7 and Q8 areprepared from cyclic anhydrides of formula XVII by reaction withorganometallic reagents of formula R¹XM:

Optionally protected compounds of Formula I wherein R² is a groupattached through an ether linkage are prepared from compounds of formulaXVIII by reaction with an alcohol R²H of formula XIX, wherein R² isselected from the subset of R² that terminates in an oxygen atom, underacidic conditions.

Alcohol intermediates XVIII are prepared by reduction of ketoneintermediates XV.

Intermediates of formula V and VII wherein L is a C₂ alkyl chain areprepared from natural and unnatural α-amino acids and by other methods(Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37,2580-2617). Likewise, intermediates of formula V and VII wherein L is aC₃ or C₄ alkyl chain are prepared from β- and γ-amino acids,respectively.

Intermediates of Formula IX wherein R³ is H and R² is a group attachedthrough a carbon atom are prepared from intermediates of Formula IXwherein R³ is OH and R² is a group attached through a carbon atom eitherby elimination of water and hydrogenation or by direct dehydroxylationfor example using Raney nickel:

Compounds of Formula I wherein R¹ is a alkoxyoxyphenyl,cycloalkoxyphenyl, cycloalkylalkoxyphenyl, or arylalkoxy group can alsobe prepared from other compounds of Formula I in which R¹ is ahydroxyphenyl group:

The invention is further defined by reference to the examples, which areintended to be illustrative and not limiting.

Representative compounds of the invention can be synthesized inaccordance with the general synthetic schemes described above and areillustrated in the examples that follow. The methods for preparing thevarious starting materials used in the schemes and examples are wellwithin the knowledge of persons skilled in the art.

The following abbreviations have the indicated meanings:

Abbreviation Meaning Aq aqueous Boc tert-butoxy carbonyl or t-butoxycarbonyl (Boc)₂O di-tert-butyl dicarbonate Brine saturated aqueous NaClCbz Benzyloxycarbonyl CbzCl Benzyl chloroformate CDI carbonyldiimidazole CH₂Cl₂ methylene chloride CH₃CN or MeCN acetonitrile Cpdcompound D day DAST diethylaminosulfur trifluoride DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexylcarbodiimide DCUN,N′-dicyclohexylurea DIAD diisopropyl azodicarboxylate DIEAN,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMFN,N-dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP2,4-dinitrophenylhydrazine EDC•HCl1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride Equivequivalents Et ethyl Et₂O ethyl ether EtOAc EtOAc Fmoc1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione h, hrhour HOBt 1-hydroxybenzotriazole HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateKHMDS potassium hexamethyldisilazane LAH or LiAlH₄ lithium aluminumhydride LC-MS liquid chromatography-mass spectroscopy LHMDS lithiumhexamethyldisilazane Me methyl MeCN acetonitrile MeOH methanol MsClmethanesulfonyl chloride Min minute MS mass spectrum NaH sodium hydrideNaHCO₃ sodium bicarbonate NaN₃ sodium azide NaOH sodium hydroxide Na₂SO₄sodium sulfate NMM N-methylmorpholine NMP N-methylpyrrolidinonePd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether Phphenyl Quant quantitative yield Rt room temperature Satd saturated SOCl₂thionyl chloride SPE solid phase extraction TBS t-butyldimethylsilylTBSCl t-butyldimethylsilyl chloride TEA triethylamine or Et₃N TEMPO2,2,6,6-tetramethyl-1-piperidinyloxy free radical Teoc1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin- 2,5-dione TFAtrifluoroacetic acid THF tetrahydrofuran Tlc thin layer chromatographyTMS trimethylsilyl TMSCl chlorotrimethylsilane or trimethylsilylchloride t_(R) retention time TsOH p-toluenesulfonic acid

Purification Methods

Prep HPLC refers to preparative reverse phase HPLC on a C-18 columneluted with a water/acetonitrile gradient containing 0.01% TFA run on aGilson 215 system.

Analytical Methods

LC-MS (3 min)Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10LC-MS (16 min)Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 14.0 10 90 15.0 10 90 15.1 90 10 16.0 90 10

Chiral HPLC

Column: Chiralpak AD-H, 0.46 cm×25 cm

Solvent A: 0.025% Diethylamine in Hexane Solvent B: Isopropanol

Flow rate: 1 mL/min.40 min. run

Gradient:

Time (min) A(%) B(%) 0 95 5 40 90 10

Example 1 (R)-tert-Butyl3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate

Step 1. (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate

(R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol,1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol,1.25 equiv) and EDC.HCl (26.3 g, 0.14 mol, 1.25 equiv) anddiisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in 400ml (400 mL) and stirred overnight at rt. The reaction mixture wasdiluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO₃(150 mL), brine (100 mL), and dried over Na₂SO₄. Concentration afforded(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate(24.42 g, 82%) as a clear oil. LC-MS (3 min) t_(R)=1.41 min, m/z 295(M+Na). ¹H NMR (CDCl₃) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H),2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33(m, 10H). Chiral HPLC indicated 100% purity. The crude product was usedfor next step without further purification.

Step 2. (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate

(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate(13.6 g, 50 mmol) was dissolved in anhydrous THF (200 mL) and cooled to−10° C. (ice/MeOH bath). Phenylmagnesium bromide solution in THF (100 mLof 1.0 M, 100 mmol, 2 equiv) was added slowly. After 15 min, thereaction mixture was warmed up to rt slowly and stirred for 1 hour.LC-MS showed the reaction was complete. 5% Aq HCl (100 mL) was addedslowly to quench the reaction and the mixture was stirred for 20 min.After separation, the aqueous layer was extracted with ether (2×200 mL).The combined organic layers were washed with satd aq NaHCO₃ (150 mL),brine (100 mL), and dried over Na₂SO₄. Concentration afforded crude(R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (16.45 g, 110%) as aclear oil which was used for the next step without further purification.LC-MS (3 min) t_(R)=1.91 min, m/z 302 (M+Na). ¹H NMR (CDCl₃) δ 7.94 (d,2H), 7.54 (t, 1H), 7.47 (t, 2H), 4.28 (br d, 1H), 4.09 (d, 1H), 3.38 (t,1H), 2.92 (br t, 1H), 2.72 (t, 1H), 2.01 (d, 1H), 1.79-1.45 (m, 3H) 1.42(s, 9H). Chiral HPLC indicated 100% purity.

Step 3. (R)-tert-butyl3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate

A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g,35.64 mmol) anhydrous toluene (120 mL) was cooled to −78° C. and(R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol,0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107mmol, 3 equiv) was added slowly. The reaction mixture was thentransferred into the freezer (˜14.2° C.) and left overnight. LC-MS (16min) showed 9:1 ratio of the R to S isomer. The mixture was cooled to 0°C. and water was added dropwise to quench the reaction. The reactionmixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water(150 mL), 5% aq HCl (100 mL), brine (100 mL), and dried over Na₂SO₄.After concentration, the crude product was purified by flashchromatography on a 120 g silica gel column eluted with a 4-35% EtOAc inhexanes gradient. The purified product was recrystallized from an etherhexanes mixture to afford (R)-tert-butyl3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) aswhite solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min)t_(R)=1.70 min; LC-MS (3 min) t_(R)=10.62 min, m/z 314 (M+Na). ¹H NMR(CDCl₃) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s,free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m,1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H).

Step 4. (R)-tert-Butyl3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate

An oven dried flask was charged with (R)-tert-butyl3-((R)-hydroxy(phenyl)methyl)-piperidine-1-carboxylate (3.18 g, 10.9mmol) and 60% NaH in mineral oil (2.19 g, 54.8, 5 equiv). The flask waspurged with N₂ gas, cooled to 0° C. and anhydrous THF (100 mL) was addedslowly. The mixture was allowed to warm to rt slowly. A solution of3-ethoxypropyl methanesulfonate (6.0 g, 32.9 mmol, 3 equiv) in anhydrousTHF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MSindicated the reaction completed. The reaction mixture was cooled to 0°C. slowly and water was added dropwise to quench the reaction. Afterseparation, the aqueous layer was extracted with ether three times. Thecombined organic layers were washed with 5% aq HCl, satd aq NaHCO₃,brine, and dried over Na₂SO₄. After concentration, the crude product waspurified by flash chromatography on a 120-g silica gel cartridge elutedwith a 0-30% EtOAc in hexanes gradient) to afford (R)-tert-butyl3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (3.70 g,90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min)t_(R)=2.38 min, m/z 400 (M+Na). ¹H NMR (CDCl₃) δ 7.26 (m, 5H), 4.39 (d,1H), 3.89 (t, 2H), 3.53-3.40 (m, 4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m,2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40-1.22 (m, 2H), 1.15 (t, 3H),1.10-0.96 (m, 1H).

Example 2 1-Phenyl-1-(piperidin-3-yl)heptan-1-ol

Step 1. tert-Butyl 3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate

To a 100-mL round bottom flask were added tert-butyl3-(benzoyl)piperidine-1-carboxylate (0.4733 g, 1.63 mmol, 1.0 equiv) andTHF (5 mL). The flask was evacuated and refilled with N₂. The mixturewas cooled with a dry ice-acetone bath and hexylmagnesium bromide (2.0Msolution in Et₂O, 2.5 mL, 5.0 mmol, 3.0 equiv) was added. The reactionmixture was allowed to slowly warm to −10° C. while stirring overnight(17 h). The mixture was quenched with saturated NH₄Cl (10 mL), extractedthree times with EtOAc, and dried over Na₂SO₄. The crude product waspurified by reversed-phase HPLC(XTerra® Prep MS C₁₈ OBD™ Column, 5 μl,19×50 mm, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8 min, flow rate 20mL/min) to give tert-butyl3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate. LC-MS (3 min)t_(R)=2.41 min, m/z 398 (M+Na⁺), 376 (MH⁺), 302, 276, 258.

Step 2. 1-Phenyl-1-(piperidin-3-yl)heptan-1-ol

A mixture of tert-Butyl3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate, obtained asdescribed above, in CH₃CN (40 mL) and 2 N HCl (40 mL) was vigorouslystirred at rt for 20 h. 60 mL of the reaction mixture was quenched withsaturated NaHCO₃, extracted three times with EtOAc, and dried overNa₂SO₄. The crude product (0.2709 g, 80% in two steps) was used withoutfurther purification. LC-MS (3 min) t_(R)=1.29 min in 3 minchromatography, m/z 276 (MH⁺).

Example 3 4-Cyclopropyl-1-phenyl-1-(piperidin-3-yl)butan-1-ols

Step 1. tert-Butyl3-((R)-1-hydroxy-1-phenylhex-5-enyl)piperidine-1-carboxylate

A stirred solution of tert-butyl 3-benzoylpiperidine-1-carboxylate (160mg, 0.55 mmol) in dry THF (2 mL) was cooled to −70° C. and4-pentenylmagnesium bromide in THF (1.8 mL of −2.5 M, 2.8 mmol) wasadded dropwise. The mixture was stirred at −78° C. and allowed to warmto rt overnight. The reaction was quenched with satd aq ammoniumchloride. The aqueous layer was extracted with Et₂O (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated to dryness. The crude material was purified by flashchromatography on a prepacked silica cartridge eluted with anEtOAc/hexanes gradient. tert-Butyl3-((R)-1-hydroxy-1-phenylhex-5-enyl)piperidine-1-carboxylate (174 mg,88%) was isolated as an oil. MS ESI +ve m/z 382 (M+Na)⁺.

Step 2. 4-Cyclopropyl-1-phenyl-1-(piperidin-3-yl)butan-1-ol

To a 0° C. solution of diethyl zinc (1.0 mL of 1M in hexane, 1 mmol) indry dichloroethane (2 mL), chloroiodomethane (0.14 ml, 2.0 mmol) wasadded dropwise over five minutes. The reaction was removed from the icebath and allowed to stir at rt for 40 min A dichloroethane solution (1mL) of tert-butyl3-((R)-1-hydroxy-1-phenylhex-5-enyl)piperidine-1-carboxylate (174 mg,0.480 mmol) was added dropwise. The reaction was allowed to stirovernight. The reaction was quenched with satd ammonium chloride. Theaqueous layer was extracted 3× with CH₂Cl₂. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and evaporated todryness. The crude material was purified via preparative HPLC (C-18column, 10 to 90% CH₃CN in H₂O containing 0.01% CF₃CO₂H over 10 min, 20mL/min) to afford the trifluoroacetic acid salt of4-cyclopropyl-1-phenyl-1-(piperidin-3-yl)butan-1-ol (32 mg, 24%). MS ESI+ve m/z 274 (M+1).

Example 4 tert-Butyl3-(hydroxy(phenyl)methyl)-3-methylpiperidine-1-carboxylate

Step 1. Tert-butyl 3-benzoyl-3-methylpiperidine-1-carboxylate

A stirred solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate(409 mg, 1.42 mmol) in dry THF (15 mL) under N₂ was cooled to −78° C. Asolution of lithium bis(trimethylsilylamide) in THF (2.84 mL of 1.0M,2.84 mmol, 2 equiv) was added dropwise. After 30 min, a solution ofiodomethane (220 μL, 3.5 mmol, 2.5 equiv) in DMPU (512 μL, 4.24 mmol,3.0 equiv) was added slowly. After 15 min, the reaction mixture wasallowed to warm to rt and stirred overnight. LC-MS showed the reactionwas complete. Brine (50 mL) was added to quench the reaction. Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×75 mL). The combined organic layers were dried over Na₂SO₄.After concentration, the crude product was purified by chromatography ona prepacked 12-g silica gel cartridge eluted with a 0-35% EtOAc inhexanes gradient to afford tert-butyl3-benzoyl-3-methylpiperidine-1-carboxylate (278 mg, 65%). LC-MS (3 min)t_(R)=1.92 min, m/z 326 (M+Na).

Step 2. tert-Butyl3-(hydroxy(phenyl)methyl)-3-methylpiperidine-1-carboxylate

tert-Butyl 3-benzoyl-3-methylpiperidine-1-carboxylate (278 mg, 0.92mmol) was dissolved in 1:1 THF/MeOH (8 mL) and NaBH₄ (70 mg, 1.84 mmol,2 equiv) was added. After stirring 30 min at rt, LC-MS showed thereaction was complete. After concentration, the residue was partitionedbetween ether and diluted (˜1%) aq HCl. The aqueous layer was separatedand extracted twice with ether. The combined organic layers were washedwith satd aq NaHCO₃, brine, dried over Na₂SO₄ and evaporated to affordcrude product which was purified by chromatography on a 12-g prepackedsilica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient toafford tert-butyl3-(hydroxy(phenyl)methyl)-3-methylpiperidine-1-carboxylate (198 mg,71%). LC-MS (3 min) t_(R)=1.83 min, m/z 328 (M+Na).

Example 5

Using procedures analogous to those described in Examples 1-4, thefollowing intermediates were prepared:

-   1-phenyl-1-(piperidin-3-yl)pentan-1-ol-   2-((3-methoxypropoxy) (phenyl)methyl)morpholine-   1-(3-fluorophenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine-   3-((3-methoxypropoxy)(3-fluorophenyl)methyl)piperidine-   5-methoxy-1-(2-phenoxyphenyl)-1-(piperidin-3-yl)pentan-1-ol-   5-methoxy-1-(piperidin-3-yl)-1-m-tolylpentan-1-ol-   1-(2,5-difluorophenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   3-((3-methoxypropoxy)(4-fluorophenyl)methyl)piperidine-   1-(3-(trifluoromethyl)phenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   5-ethoxy-1-phenyl-1-(piperidin-3-yl)pentan-1-ol-   3-((3-ethoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   3-((3-methoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   4-methoxy-1-phenyl-1-(piperidin-3-yl)butan-1-ol-   3-((4-methoxybutoxy)(phenyl)methyl)piperidine-   3-((3-methoxypropoxy)(piperidin-3-yl)methyl)benzonitrile-   4-ethoxy-1-phenyl-1-(piperidin-3-yl)butan-1-ol-   3-((3-propoxypropoxy) (phenyl)methyl)piperidine-   3-((2-cyclopropylethoxy)(phenyl)methyl)piperidine-   4,4,4-trifluoro-1-(piperidin-3-yl)-1-m-tolylbutan-1-ol-   3-((3-ethoxypropoxy)(phenyl)methyl)piperidine-   3-((3-methoxypropoxy)(2,4-difluorophenyl)methyl)piperidine-   1-(3,4-difluorophenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   1-(3-isopropylphenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   1-(3-chlorophenyl)-5-cyclopropyl-1-(piperidin-3-yl)pentan-1-ol-   1-(2-(p-tolyloxy)-5-methylphenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   1-(5-chloro-2-phenoxyphenyl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol-   (3-chlorophenyl)(piperidin-3-yl)methanol-   1-(3-chlorophenyl)-1-(piperidin-3-yl)ethanol-   1-(3-chlorophenyl)-1-(piperidin-3-yl)propan-1-ol-   1-(3-chlorophenyl)-1-(piperidin-3-yl)butan-1-ol-   1-(3-chlorophenyl)-1-(piperidin-3-yl)pentan-1-ol-   5-methoxy-1-(3-methylpiperidin-3-yl)-1-phenylpentan-1-ol-   (S)-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-methoxypropoxy) (2-fluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(3-fluorophenyl)methyl)piperidine-   (S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-m-tolylpentan-1-ol-   (S)-1-(2,5-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(4-fluorophenyl)methyl)piperidine-   (S)-1-(3-(trifluoromethyl)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidine-   (S)-5-ethoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(3,4-difluorophenyl)methyl)piperidine-   (S)-4-methoxy-1-phenyl-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-3-((R)-(4-methoxybutoxy)(phenyl)methyl)piperidine-   3-((R)-(3-methoxypropoxy)((R)-piperidin-3-yl)methyl)benzonitrile-   (S)-4-ethoxy-1-phenyl-1-((R)-piperidin-3-yl)butan-1-ol-   (R)-3-((R)-(3-propoxypropoxy)(phenyl)methyl)piperidine-   (R)-3-((R)-(2-cyclopropylethoxy)(phenyl)methyl)piperidine-   (S)-4,4,4-trifluoro-1-((R)-piperidin-3-yl)-1-m-tolylbutan-1-ol-   (R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-   (R)-3-((R)-(3-methoxypropoxy)(2,4-difluorophenyl)methyl)piperidine-   (S)-1-(3,4-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-isopropylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(3-chlorophenyl)-5-cyclopropyl-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(2-(p-tolyloxy)-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-1-(5-chloro-2-phenoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol-   (S)-(3-chlorophenyl)((R)-piperidin-3-yl)methanol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)ethanol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)propan-1-ol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol-   (S)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)pentan-1-ol-   (R)-3-((R)-(2,3-dichlorophenyl)(3-ethoxypropoxy)methyl)piperidine-   (R)-3-((R)-(3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-chloro-2-fluorophenyl)    (3-ethoxypropoxy)methyl)piperidine-   (R)-3-((R)-(3-chlorophenyl)(3-ethoxypropoxy)methyl)piperidine-   (R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)piperidine-   (R)-3-((R)-(3-ethoxypropoxy)(m-tolyl)methyl)piperidine-   (S)-4-cyclopropyl-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)butan-1-ol-   (S)-1-(3-chlorophenyl)-4-cyclopropyl-1-((R)-piperidin-3-yl)butan-1-ol    and-   (S)-4-cyclopropyl-1-(3-fluorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol.

Example 63-((2-Bromophenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine

Step 1. Ethyl1-(2-(trimethylsilyl)ethylsulfonyl)piperidine-3-carboxylate

A 1 L flask equipped with a dropping funnel was charged with2-(trimethylsilylethane)-sulfonyl chloride (7.5 g, 0.0374 mol, 1.0equiv) and CH₂Cl₂ (150 mL). The flask was cooled to 0° C. and thedropping funnel was charged with a solution of racemic ethylpiperidine-3-carboxylate (7.34 g, 0.0467 mol, 1.25 equiv) anddiisopropylethyl amine (12.1 g, 0.0935 mol, 2.5 equiv) in CH₂Cl₂ (50mL). The solution of the amines was added and the resulting mixture wasstirred for 3 h with concomitant warming to rt temperature. Analysis ofthe mixture by LC-MS showed a signal for the desired product. Thereaction mixture was quenched by addition of 1.0 M HCl (100 mL). Thelayers were separated and the organic layer washed with additionalaqueous HCl, then brine. It was dried over Na₂SO₄, filtered andevaporated to yield ethyl1-(2-(trimethylsilyl)ethanesulfonyl)piperidine-3-carboxylate (10.63 g,88%) as an amber syrup which was of sufficient purity to use in the nextstep. ¹H NMR (CDCl₃) δ −0.01 (s, 9H), 0.96 (m, 2H), 1.23 (t, 3H),1.4-1.6 (m, 4H), 1.78 (M, 1H), 2.03 (m, 1H), 2.53 (m, 1H), 2.79 (m, 2H),2.95 (d of d, 1H), 3.61 (m, 1H), 3.82 (m, 1H), 4.08, (q, 2H).

Step 2. (1-(2-(Trimethylsilyl)ethylsulfonyl)piperidin-3-yl)methanol

Ethyl 1-(2-(trimethylsilyl)ethanesulfonyl)piperidine-3-carboxylate (9.00g, 28 mol) was dissolved in THF (200 mL) in a three-neck 500 mL flaskand cooled to 0° C. A solution of LiBH₄ (2.0 M in THF, 28 mL, 0.056 mol,2.0 equiv) was added via addition funnel. The mixture was allowed towarm to rt and stir for 15 h. Significant amounts of the starting esterremained; an additional charge of the LiBH₄ solution (28 mL, 0.056 mol)was added and the mixture stirred for an additional 17 h. After thisperiod analysis by LC-MS showed consumption of the starting ester. Themixture was cooled to 0° C. and the excess LiBH₄ was quenched bydropwise addition of MeOH (100 mL). The volatile materials were removedand the residue partitioned between ether (100 mL) and 1.0 M aq HCl (100mL). The layers were separated and the aqueous layer extracted withadditional ether (3×50 mL). The combined organic extracts were washedwith brine and dried over Na₂SO₄. The clear solution was evaporated toyield (1-(2-(trimethylsilyl)ethylsulfonyl)piperidin-3-yl)methanol (5.25g, 67%) as a white solid which was of sufficient purity to use in thenext step. ¹H NMR (CDCl₃) δ 0.00 (s, 9H), 0.95 (m, 2H), 1.21 (m, 1H),1.5-8 (m, 5H), 2.75-2.82 (m, 3H), 2.91 (t of d, 1H), 3.53 (m, 2H), 3.62(d of d, 1H).

Step 3. 1-(2-(Trimethylsilyl)ethylsulfonyl)piperidine-3-carbaldehyde

A three neck 500-mL flask equipped with a dropping funnel was chargedwith of anhydrous CH₂Cl₂ (100 mL) and oxalyl chloride (2.64 g, 20.7mmol, 1.1 equiv). The solution was cooled to −78° C. under nitrogen. Asolution of DMSO (2.93 g, 37.6 mmol, 2.0 equiv) in CH₂Cl₂ (10 mL) wasadded dropwise to the oxalyl chloride over a 15 minute period, and theresulting solution stirred for 30 min at −78° C. A solution of1-(2-(trimethylsilyl)ethanesulfonyl)-3-hydroxymethylpiperidine (5.25 g,18.8 mmol, 1.0 equiv) in CH₂Cl₂ (30 mL) was added dropwise over a 30 minperiod, and the resulting mixture stirred for 30 min at −78° C.Triethylamine (9.51 g, 94.4 mmol, 5.0 equiv) was added dropwise to themixture over a 30 min period. The resulting white slurry was allowed towarm to 0° C. and stir for 30 min. Analysis of the mixture by LC-MSshowed consumption of the alcohol. Water (200 mL) was added and thelayers were separated. The organic layer was washed with brine and driedover Na₂SO₄. The aldehyde was purified by flash chromatography on 120 gof silica, eluting with 0 to 50 EtOAc in hexanes. Fractions containingthe desired aldehyde were visualized by staining with2,4-dinitrophenylhydrazine on silica gel. Removal of the solventafforded 1-(2-trimethylsilyl(ethanesulfonyl))piperidine-3-carbaldehyde(3.8 1 g, 73%) as a white solid. ¹H NMR (CDCl₃) δ −0.15 (s, 9H), 0.96(m, 2H), 1.5-1.77 (m, 4H), 1.95 (M, 1H), 2.54 (m, 1H), 2.82 (m, 2H),2.95 (m, 1H), 3.17 (d of d, 1H), 3.44 (m, 1H), 3.72 (m, 1H), 9.64 (s,1H).

Step 4.(2-Bromophenyl)(1-(2-(trimethylsilyl)ethylsulfonyl)piperidin-3-yl)methanol

A three neck 200-mL flask was charged with anhydrous THF (150 mL) and1-bromo-2-iodobenzene (5.81 g, 20.5 mmol, 1.5 equiv), and cooled to −40°C. Isopropyl magnesium bromide (1.0 M in THF, 19.9 mL, 19.9 mmol, 1.45equiv) was added to the solution via syringe at a rate such that theinternal temperature did not rise above −35° C. An aliquot was removed,quenched with water and analyzed by LC-MS. The observed amount ofbromobenzene showed >90% conversion to the desired Grignard reagent. Asolution of1-(2-trimethylsilyl-(ethanesulfonyl))piperidine-3-carbaldehyde (3.8 g,13.7 mmol) in 20 mL of THF was added to solution containing the Grignardreagent at such a rate that the internal temperature did not rise above−35° C. The mixture was stirred for 1 h at −40° C.; after this periodLC-MS analysis of an aliquot showed consumption of the aldehyde andformation of two peaks with the desired mass, consistent with formationof two diastereomers. The mixture was quenched with methanol and the THFremoved in vacuo. The resulting solid was partitioned between EtOAc andwater, and filtered through a pad of Celite to remove a sticky whitesolid. The layers were separated and the aqueous layer was extractedwith additional EtOAc. The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and evaporated. The mixture ofalcohols was purified by flash chromatography on 120 g silica, elutingwith 0 to 50% EtOAc in hexanes. No attempt was made to separate the twodiastereomers. This afforded(2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol(3.64 g, 61%) as a white foam. ¹H NMR (CDCl₃) δ 0.01 (s, 9H), 0.95-2.06(m, 8H), 2.6-3.0 (m, 6H), 3.6-3.9 (m, 3H), 4.96 (bs, 1H), 7.13 (m, 1H),7.29 (m, 1H), 7.44 (m, 2H).

Step 5.3-((2-Bromophenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine

A 250-mL three neck flask fitted with a reflux condenser was chargedwith NaH (60% in mineral oil, 644 mg of material, 16.1 mmol, 5.0 equiv).Anhydrous THF (80 mL) was added. A solution of(2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol(1.4 g, 3.22 mmol, 1.0 equiv) in 10 mL of THF was slowly added viasyringe. After cessation of hydrogen evolution, a solution of3-methoxypropyl methanesulfonate (2.2 g, 12.8 mmol, 4.0 equiv) in 10 mLof THF was added and the resulting mixture was heated to reflux. After1.0 h the signals for the starting material in the LC-MS were consumedand a new peak with M+Na for the desired product was observed. Themixture was allowed to cool to rt and excess NaH was quenched withwater. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic fractions were washed with brine andpurified by flash chromatography on silica gel (40 g) eluting with 0-25%EtOAc in hexanes. This afforded3-((2-bromophenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine(1.2 g, 73%) as a clear syrup containing a mixture of two diastereomers.No attempt was made to separate the diastereomers. MS ESI +ve m/z 506(M+1).

Example 71-Methanesulfonyl-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidine

1-methanesulfonyl-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidinewas prepared following procedures analogous to those used in Example 6using methanesulfonyl chloride in Step 1.

Example 8N-(2-Trimethylsilyl)ethanesulfonyl)-3-((methoxypropoxy)(2-allylphenyl)methyl)piperidine

A tube designed for a microwave reactor was charged with1-(2-(trimethylsilyl)-ethanesulfonyl)-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidine(100 mg, 0.197 mmol, 1.0 equiv), Pd₂(dba)₃ (10 mg, 0.0099 mmol, 0.05equiv), P(^(t)Bu₃) (10% in hexanes, 100 μL, 0.02 mmol, 0.10 equiv),allyltributyltin (68 mg, 0.206 mmol, 1.05 equiv), andN-methylpyrrolidinone (1.0 mL). The tube was sealed and the resultingpurple solution was degassed by three evacuate/N₂ backfill cycles, thenplaced in a microwave reactor and heated to 120° C. for 20 min. Theresulting brown solution was analyzed by LC-MS, which showed consumptionof the starting bromide and formation of a new peak with desired mass.Solid KF.H₂O (500 mg) was added, and the mixture stirred for 30 min inthe air. The residue was partitioned between EtOAc and water. The layerswere separated and the aqueous layer extracted with additional EtOAc.The combined organic extracts were washed with brine, dried over Na₂SO₄and evaporated. The product was isolated by flash chromatography on 4 gsilica, eluting with 0 to 20% EtOAc in hexanes.N-(2-Trimethylsilyl)ethane-sulfonyl)-3-((methoxypropoxy)(2-allyl)phenyl)methyl)-piperidinewas isolated as a pale yellow oil (42 mg, 43%). MS ESI +ve m/z 491(M+Na⁺).

Example 93-((2-(Cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)piperidine

Step 1.3-((2-(Cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine

A tube designed for a microwave reactor was charged with the1-methanesulfonyl-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidine(100 mg, 0.197 mmol, 1.0 equiv), Pd₂(dba)₃ (10 mg, 0.0099 mmol, 0.05equiv), P(^(t)Bu₃) (10% in hexanes, 100 μL, 0.02 mmol, 0.10 equiv),cyclopropylacetylene (70% solution in toluene, 70 μL, 0.60 mmol, 3.0equiv), and piperidine (2.0 mL). The tube was sealed and the resultingpurple solution degassed by three evacuate/N₂ backfill cycles, thenplaced in a microwave reactor and heated to 130° C. for 10 min. Theresulting yellow solution containing dark solids was analyzed by LC-MS(3 min), which showed consumption of the starting bromide and formationof a new peak at t_(R)=2.43 min with m/z=M+Na for the desired product.The contents were transferred to a flask and excess piperidine wasremoved in vacuo. The residue was partitioned between EtOAc and 1.0 MHCl. The yellow organic layer was washed with brine, dried over Na₂SO₄and evaporated. The product was isolated by flash chromatography on 12 gsilica, eluting with 0 to 20% EtOAc in hexanes.3-((2-(cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine(68 mg, 70%) was isolated as a pale brown oil. MS ESI +ve m/z 515(M+Na⁺).

Step 2.3-((2-(Cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)piperidine

A 50-mL round bottom flask was charged with3-((2-(cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine(63 mg, 0.128 mmol, 1.0 equiv), tetraethylammonium fluoride (63 mg,0.422 mmol, 3.4 equiv) and acetonitrile (5 mL). The mixture was heatedto 65° C. for 17 h. Analysis of the yellow reaction mixture by LC-MSshowed consumption of the protected piperidine and formation of a newsignal containing the mass of the desired product. The acetonitrile wasremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ and water. The layers were separated and the aqueous layer wasextracted twice with additional CH₂Cl₂. The combined organic layers werewashed with brine, dried over Na₂SO₄ and evaporated, yielding3-((3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)piperidine(40 mg, 95%). No additional purification was attempted. MS ESI +ve m/z328 (M+H⁺).

Example 10 3-((Methoxypropoxy)(2-phenyl)phenyl)methyl)piperidine

Step 1.3-(Biphenyl-2-yl(3-methoxypropoxy)methyl)-1-(methylsulfonyl)piperidine

A tube designed for a microwave reactor was charged with1-methanesulfonyl-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidine(200 mg, 0.0.476 mmol, 1.0 equiv), PdCl₂(dppf) (21 mg, 0.0.238 mmol,0.05 equiv), Cs₂CO₃ (511 mg, 1.57 mmol, 3.3 equiv), phenylboronic acid(87 mg, 0.714 mmol, 1.5 equiv) and 4 mL of 1,4-dioxane. The tube wassealed and the resulting yellow solution degassed by three evacuates/N₂backfill cycles, then placed in a microwave reactor and heated to 120°C. for 15 min. The contents were transferred to a flask and volatilematerials removed in vacuo. The residue was partitioned between CH₂Cl₂and water. The yellow organic layer was washed with brine, dried overNa₂SO₄ and evaporated. The product was purified by flash chromatographyon 4 g silica, eluting with 0 to 50% EtOAc in hexanes.3-(Biphenyl-2-yl(3-methoxypropoxy)methyl)-1-(methylsulfonyl)piperidinewas isolated as an off white solid (82 mg, 91%). ¹H NMR (CDCl₃) δ0.8-1.8 (m, 8H), 2.25-2.5 (m, 4H), 2.85 (s, 3H), 3.25-3.55 (m, 4H), 3.25(s, 3H), 3.55 and 3.62 (bd, 1H), 4.08 and 4.13 (d, 1H), 7.07-7.56 (m,9H).

Step 2. 3-(Biphenyl-2-yl(3-methoxypropoxy)methyl)piperidine

N-(methane-sulfonyl)-3-((methoxypropoxy)(2-phenyl)phenyl)methyl)piperidine(182 mg, 0.436 mmol) was dissolved in dry toluene (7 mL) in a 50 mLflask and stirred under a nitrogen atmosphere. Red-Al (65% in toluene,0.30 mL, 1.3 mmol, 3.0 equiv) was added via syringe and the mixture washeated to 78° C. for 15 h. After this period LC-MS showed consumption ofthe starting material and formation of a new signal with m/z 340 (M+H⁺).The mixture was allowed to cool to rt and excess Red-Al was quenched bydropwise addition of 3 mL of satd NaCl solution. The mixture was stirredfor 20 min, then filtered through a pad of Celite. The pad was washedwith additional toluene and the filtrate was washed with brine, driedover Na₂SO₄, filtered and evaporated to yield3-(biphenyl-2-yl(3-methoxypropoxy)methyl)piperidine (146 mg, ˜99%) as apale yellow oil. This material was used directly in the subsequentsteps. ¹H NMR (CDCl₃) δ 0.65-1.8 (m, 6H), 1.8-2.5 (m, 3H), 2.83 (bd,1H), 3.05-3.2 (m, 1H), 3.18 (2, 3H), 3.38-3.44 (m, 4H) 4.06-4.12 (m,1H), 7.15 (m, 2H), 7.3-7.55 (m, 7H).

Example 111-(2-(Trimethylsilyl)ethanesulfonyl)-3-((3-methoxypropoxy)(2-(2-cyclohexylethyl)phenyl)methyl)piperidine

A sealed tube designed for a microwave reactor was filled with nitrogenand charged with vinylcyclohexane (66 mg, 0.595 mmol, 5.0 equiv) 9-BBN(0.5 M solution in THF, 1.07 mL, 4.5 equiv) and the clear solution wasstirred overnight at rt. The flask was briefly opened and Cs₂CO₃ (213mg, 0.119 mmol, 3.3 equiv), PdCl₂(dppf) (11 mg, 0.119 mmol, 0.05 equiv),1-(2-(trimethylsilyl)ethanesulfonyl)-3-((3-methoxypropoxy)(2-bromophenyl)methyl)-piperidine(100 mg, 0.197 mmol, 1.0 equiv), and dioxane (4 mL) added. The tube wasdegassed by three evacuate/N₂ backfill cycles, then placed in a CEMmicrowave reactor and heated to 120° C. for 10 min. The solvent wasremoved and the product was extracted with EtOAc and filtered through apad of Celite. The product was purified by flash chromatography on 12 gof silica, eluting with 0 to 27% EtOAc in hexanes, to afford1-(2-(trimethylsilyl)ethanesulfonyl)-3-((3-methoxypropoxy)(2-(2-cyclohexylethyl)phenyl)methyl)piperidine(82%) as a mixture of diastereomers. ¹H NMR (CDCl₃) δ 0.02 (s, 9H),0.8-1.9 (m, 24H), 2.5-2.8 (m, 4H), 3.3-4.4 (m, 11H), 7.1-7.3 (m, 4H). MSESI +ve m/z 561 (M+Na⁺).

Example 12 (S)-2-(Trimethylsilyl)ethyl2-amino-3-cyclohexylpropylcarbamate

Step 1. (S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropylmethanesulfonate

A solution of (S)—N-Boc-2-amino-3-cyclohexylpropanol (20 g, 0.078 mol)in CH₂Cl₂ (400 mL) and triethylamine (19.6 g, 0.195 mol) was cooled to−20° C. Methanesulfonyl chloride (19.5 g, 0.171 mol) was added with fastdropwise addition maintaining the internal temperature at −20° C. Thereaction mixture was stirred at −20° C. for an additional 30 min thenfor 1 h at 0° C. and then quenched with ice-cold water (200 mL). Themixture was extracted with CH₂Cl₂ (3×100 mL), washed with water (3×50mL), dried over Na₂SO₄, concentrated to give the crude(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate(23.3 g, 90%), which was used for the next reaction without furtherpurification. ¹H NMR (400 MHz, CDCl₃): 4.93 (m, 1H), 4.60 (d, J=7.6 Hz,1H), 3.67 (m, 2H), 3.12 (s, 3H), 1.87-1.50 (m, 5H), 1.45 (s, 9H),1.40-0.72 (m, 8H), MS (E/Z): 336 (M+H⁺).

Step 2. (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate

To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropylmethanesulfonate (23.3 g, 0.070 mol) in anhydrous DMF (300 mL) was addedsolid NaN₃ (13.5 g, 0.21 mol). The reaction mixture was heated at 80° C.overnight. After cooling to rt, the reaction solution was diluted withEtOAc (1200 mL) and water (400 mL). The organic phase was separated andwashed with brine (3×300 mL), dried over Na₂SO₄ and evaporated. Theresidue was purified by column chromatography on silica gel to give(S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate as a clear oil(13.6 g, 69%). ¹H NMR (400 MHz, CDCl₃): 4.45 (d, J=8.0 Hz, 1H), 3.84 (m,1H), 3.45 (m, 1H), 3.31 (m, 1H), 1.81-1.60 (m, 5H), 1.45 (s, 9H),1.40-0.78 (m, 8H). MS (E/Z): 383 (M+H⁺).

Step 3. (S)-test-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate

A mixture of (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate(13.6 g, 0.048 mol) and Pd/C (1.4 g) in methanol (200 mL) washydrogenated with a balloon overnight. The mixture was filtered througha pad of Celite and the solvent was removed to give (S)-tert-butyl1-amino-3-cyclohexylpropan-2-ylcarbamate (10.5 g, 86%), which was usedin the next step without purification. ¹H NMR (400 MHz, CDCl₃): 4.52 (d,J=8.4 Hz, 1H), 3.68 (m, 2H), 2.73 (dd, J=13.6&4.4 Hz, 1H), 2.58 (dd,J=13.6&6.0 Hz, 1H), 1.81 (m, 1H), 1.65 (m, 4H), 1.42 (s, 9H), 1.40-1.00(m, 6H), 1.00-0.70 (m, 2H). MS (E/Z): 257 (M+H⁺).

Step 4. (S)-tert-Butyl1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate

To a vigorously stirred biphasic solution of (S)-tert-butyl1-amino-3-cyclohexylpropan-2-ylcarbamate (10.5 g, 0.041 mol), K₂CO₃(10.2 g, 73.8 mol), H₂O (60 mL), and CH₂Cl₂ (120 mL) was added1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (TeocOSu)(11.14 g, 0.043 mol). The mixture was stirred for 2 h at rt, and thenthe reaction was washed with brine (3×20 mL), dried over Na₂SO₄,decanted, stripped, and separated on 50 g of SiO₂ to give (S)-tert-butyl1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate(8.5 g, 52%) as a clear oil. ¹H NMR (400 MHz, CDCl₃): 5.52 (brs, 1H),4.42 (brs, 1H), 4.11 (m, 2H), 3.73 (brs, 1H), 3.30-3.03 (m, 2H),1.81-1.50 (m, 5H), 1.43 (s, 9H), 1.42-1.02 (m, 6H), 1.02-0.76 (m, 4H),0.03 (s, 9H); MS (E/Z): 401 (M+H⁺).

Step 5. (S)-2-(Trimethylsilyl)ethyl 2-amino-3-cyclohexylpropylcarbamate

(S)-tert-butyl1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate(8.5 g, 0.0213 mol) was dissolved into a minimal volume of ethyl ether(120 mL) and added to a solution of tosic acid (4.46 g, 0.023 mol) in 25mL of absolute EtOH. This solution was placed on a rotary evaporator andethyl ether was removed at ambient temp. The flask was then lowered intothe water bath (temperature: 60° C.) and the selective de-protection ofthe Boc group proceeded concurrently with removal of the remainder ofsolvent. The reaction was completed by 2 h and gave an off-white solid.This material was cooled to rt and dissolved in 100 mL of a mixtureEtOH:H₂O (1:1, v/v). This was washed with hexanes:EtOAc (5:1, v/v, 3×12mL), basified with 1N NaOH (pH>10), and extracted with EtOAc (3×50 mL).The combined organic extracts were washed (3×5 mL 1N NaOH, 3×5 mLbrine), dried, decanted and stripped to give the free base of(S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpropylcarbamate (5.24 g,82%). ¹H NMR (400 MHz, CDCl₃): 5.09 (brs, 1H), 4.14 (t, J=8.4 Hz, 2H),3.23 (m, 1H) 2.88 (m, 2H), 1.75-1.48 (m, 5H), 1.5-0.75 (m, 10H), 0.05(s, 9H). MS (E/Z): 301 (M+H⁺).

Example 13 (S)-2-(trimethylsilyl)ethyl2-amino-3-cyclohexylpropyl(methyl)carbamate

Step 1. (S)-tert-Butyl 1-cyclohexyl-3-(methylamino)propan-2-ylcarbamate

(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (28g, 83.6 mmol) was dissolved into a solution of methylamine in ethanol(about 30% by weight, 300 mL). The reaction was heated at 50-60° C.overnight and concentrated in vacuo. The residue was dissolved in EtOAc,washed with brine (2×100 mL), dried over MgSO₄, and concentrated to givethe crude product. This crude product was purified by flashchromatography (AcOEt:Hex.=2:1 first, then EtOAc: MeOH=1:1) to affordpure (S)-tert-butyl 1-cyclohexyl-3-(methylamino)propan-2-ylcarbamate(10.6 g, 47%). ¹H NMR (400 MHz, CDCl₃): 4.81 (brs, 1H), 3.89 (m, 1H),2.77 (m, 2H), 2.54 (s, 3H), 2.44 (m, 2H), 1.78 (m, 1H), 1.67 (m, 4H),1.44 (s, 9H), 1.50-1.10 (m, 6H), 1.00-0.77 (m, 2H), 0.05 (s, 9H). MS(E/Z): 271 (M+H⁺).

Step 2. (S)-tert-butyl1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate

To a vigorously stirred 2-phase solution of (S)-tert-butyl1-cyclohexyl-3-(methylamino)propan-2-ylcarbamate (7.25 g, 0.027 mol),K₂CO₃ (6.66 g, 0.048 mol), H₂O (40 mL) and CH₂Cl₂ (80 mL) was added1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (TeocOSu)solid (7.3 g, 0.028 mol). After stirring for 2 h at rt, the reaction wasadded to CH₂Cl₂ (200 mL), washed with satd aq NaHCO₃ (3×15 mL) thenbrine (3×15 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography on 40 g of silica gel to give(S)-tert-butyl1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamateas a clear oil (5.78 g, 50%). ¹H NMR (400 MHz, CDCl₃) δ 4.50 (d, J=7.6Hz, 1H), 4.15 (t, J=7.6 Hz, 2H), 3.89 (m, 1H), 3.56-2.95 (m, 2H),2.92&2.90 (s, 3H), 1.82 (m, 1H), 1.66 (m, 4H), 1.41 (s, 9H), 1.50-1.10(m, 6H), 1.00-0.70 (m, 4H), 0.01 (s, 9H). MS (E/Z): 415 (M+H⁺).

Step 3. (S)-2-(Trimethylsilyl)ethyl2-amino-3-cyclohexylpropyl(methyl)carbamate

(S)-tert-butyl1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate(5.78 g, 0.014 mol) was dissolved into a minimal volume of ethyl ether(100 mL) and added to a solution of TsOH (2.92 g, 0.0154 mol) in 20.0 mLof absolute EtOH. This solution was placed on a rotary evaporator andthe Et₂O was removed at ambient temp. The flask was then lowered intothe water bath (temperature: 60° C.) and the selective de-protection ofthe BOC group proceeded concurrently with removal of the remainder ofthe solvent. The reaction was completed by 2 h and gave an off-whitesolid, which was washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basifiedwith 1N NaOH (pH>10), and extracted with ethyl ether (3×50 mL). Thecombined organic extracts were washed with 1N NaOH (3×5 mL) and brine(3×5 mL),dried, decanted and stripped to give the free base of(S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpropyl(methyl)carbamate(3.5 g, 80%). ¹H NMR (400 MHz, CDCl₃): 4.15 (t, J=8.4 Hz, 2H), 3.10 (m,3H), 2.91 (s, 3H), 1.78-1.56 (m, 5H), 1.50-1.00 (M, 6H), 1.00-0.70 (m,4H), 0.01 (s, 9H). MS (E/Z): 315 (M+H⁺).

Example 14(S)-[2-Amino-3-(4,4-difluoro-cyclohexyl)-propyl]-methyl-carbamic acid2-trimethylsilanyl-ethyl ester

Step 1. (S)-tert-Butyl1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate

To a solution of (S)-methyl2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propanoate (28.6g, 0.089 mol), prepared as described in U.S. Pat. No. 5,688,946, inethanol (600 mL) at 0° C. was added NaBH₄ (27.1 g, 0.713 mol) inportions while the temp. was maintained at 0-5° C. The mixture wasstirred for 2-3 h at rt and then evaporated. The residue was partitionedbetween water and EtOAc. The organic layer was washed with H₂O andbrine, dried over Na₂SO₄ and evaporated to give (S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (25.7 g, 99%),which was used in the next step without purification. ¹H NMR (400 MHz,CDCl₃): 4.61 (d, J=7.6 Hz, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.45-1.10(m, 11H), 1.44 (s, 9H); MS (E/Z): 295 (M+H⁺).

Step 2.(S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propylmethanesulfonate

To a solution of (S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (25.7 g, 0.088mol) in dry CH₂Cl₂ (300 mL) was added Et₃N (35.4 g, 46.2 mL) at 0 to −5°C. A solution of methanesulfonyl chloride (20.1 g, 0.1754 mol) in dryCH₂Cl₂ (150 mL) was added dropwise at the same temperature. Afteraddition, the mixture was allowed to warm to rt gradually. 300 mL ofwater was added and the aqueous layer was extracted with CH₂Cl₂ (3×100mL). The combined organic layers were washed with 10% aq citric acid,satd aq NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentratedto give methanesulfonic acid(S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propylmethanesulfonate (28.8 g, 89%), which was used in the next step withoutpurification. ¹H NMR (400 MHz, CDCl₃): 4.57 (d, J=6.8 Hz, 1H), 4.27 (m,1H), 4.16 (m, 1H), 3.97 (m, 1H), 3.03 (s, 3H), 2.40-1.20 (m, 11H), 1.44(s, 9H); MS (E/Z): 372 (M+H⁺).

Step 3. (S)-tert-Butyl1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate

(S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propylmethanesulfonate (28.8 g, 0.077 mol) was dissolved in alcoholic ofmethylamine solution (350 mL) and the reaction was warmed at 50-60° C.overnight. The reaction mixture was cooled to rt and the solvent wasremoved under reduced pressure to give an oil, which was dissolved intoEtOAc, washed with water twice and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography to afford(S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate (8.1 g,34.4%). ¹H NMR (400 MHz, CDCl₃): 5.12 (m, 1H), 4.97 (m, 1H), 3.82 (m,1H), 3.63 (dd, J=14.4&4.4 Hz, 1H), 3.45 (dd, J=14.4&9.2 Hz, 1H),2.76&2.74 (s, 1H), 2.20-1.20 (m, 11H), 1.44 (s, 9H); MS (E/Z): 307(M+H⁺).

Step 4. (S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate

Solid 1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione(TeocOSu, 7.2 g, 0.0278 mol) was added to a vigorously stirred 2-phasesolution of (S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate (8.1 g,0.0265 mol), K₂CO₃ (11.85 g, 0.0477 mol), H₂O (32 mL) and CH₂Cl₂ (64mL). After stirring for 2 h at rt, the reaction was taken up in CH₂Cl₂(200 mL) washed with satd aq NaHCO₃ (3×15 mL), then brine (3×15 mL),dried over Na₂SO₄ and evaporated to give an oil. Chromatography onsilica gel gave (S)-tert-butyl1-(4,4-difluorocyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate(6.25 g, 52.4%). ¹H NMR (400 MHz, CDCl₃): 4.58 & 4.32 (m, 1H), 4.12 (t,J=9.6 Hz, 2H) 3.89 (m, 1H), 3.40 (m, 1H), 3.05 (m, 1H), 2.89 (s, 3H),2.10-1.00 (m, 11H), 0.97 (t, J=9.6 Hz, 2H), 1.44 (s, 9H), 0.03 (s, 9H);MS (E/Z): 451 (M+H⁺).

Step 5. (S)-2-(trimethylsilyl)ethyl2-amino-3-(4,4-difluorocyclohexyl)propyl(methyl)carbamate

(S)-tert-Butyl1-(4,4-difluorocyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate(6.25 g, 0.0139 mol) was dissolved in a minimal volume of ether (100 mL)and added to a solution of toluenesulfonic acid (2.71 g, 0.0142 mol) inabsolute EtOH (20 mL). This solution was placed on a rotary evaporatorand the Et₂O was removed at ambient temp. The flask was then loweredinto the water bath (temperature: 60° C.) and the selective removal ofthe Boc group proceeded concurrently with removal of the remainder ofsolvent. The reaction was completed by 2 h and gave a white solid, whichwas washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basified with 1N NaOH(pH>10), and extracted with Et₂O (3×50 mL) The combined Et₂O extractswere washed with 1N aq NaOH (3×5 mL), brine (3×5 mL), dried, decantedand stripped to give the free base (S)-2-(trimethylsilyl)ethyl2-amino-3-(4,4-difluorocyclohexyl)propyl(methyl)carbamate (3.68 g, 76%).¹H NMR (400 MHz, CD₃OD): 4.17 (t, J=8.4 Hz, 2H), 3.15 (m, 1H), 2.93 (s,3H), 2.61 (dd, J=12.0 & 4.0 Hz, 1H), 2.36 (dd, J=12.0 & 8.4 Hz, 1H),2.12-1.16 (m, 11H), 1.00 (t, J=8.4 Hz, 2H), 0.04 (s, 9H); MS (E/Z): 351(M+H⁺).

Example 15 Benzyl (2S,3S)-3-amino-4-cyclohexylbutan-2-ylcarbamate

Step 1. tert-Butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate

To a solution of tert-butyl(S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.63 g, 2.5 mmol)and triethylamine (0.65 mL, 5 mmol) in methanol (15 mL) was added Pd/C(0.1 g), and the mixture was hydrogenated under 30 psi pressure at rtovernight. The mixture was filtered and the filtrate was concentrated togive tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44g, 70%). ¹H NMR (400 MHz, CDCl₃): 4.48 (brs, 1H), 3.78 (m, 2H), 2.30(brs, 1H), 1.82 (m, 1H), 1.66 (m, 4H), 1.45 (s, 9H), 1.40-1.00 (m, 6H),1.10 (d, J=6.4 Hz, 3H), 1.00-0.70 (m, 2H); MS (E/Z): 272 (M+H⁺).

Step 2. Tert-butyl(2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-ylcarbamate

To a solution of tert-butyl(2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 1.62 mmol) indry CH₂Cl₂ (10 mL) was added Et₃N (0.71 g, 7 mmol, 4 eq) at 0 to −5° C.A solution of methanesulfonyl chloride (0.8 g, 7 mmol, 2 eq) in dryCH₂Cl₂ (5 mL) was added dropwise at the same temperature. The mixturewas allowed to warm to rt gradually. TLC showed that the startingmaterial had disappeared. Water (30 mL) was added. The aqueous layer wasextracted with CH₂Cl₂ (3×20 mL). The combined organic layers was washedwith 10% aq citric acid, satd aq NaHCO₃ and brine, then dried overNa₂SO₄, filtered and concentrated to give tert-butyl(2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-yl-carbamate (0.46 g,81%), which was used in the next step without purification.

Step 3. Tert-butyl (2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate

tert-Butyl(2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-ylcarbamate (0.46 g,1.32 mmol) was dissolved into anhydrous DMF (10 mL), solid NaN₃ (0.26 g,4 mmol) was added and the reaction mixture was heated to 80° C.overnight. The reaction mixture was cooled to rt and diluted with EtOAc(100 mL) and water (30 mL). The organic phase was washed with water(3×30 mL), dried over Na₂SO₄ and evaporated. The residue was separatedby chromatography on a silica gel column to give tert-butyl(2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate (0.215 g, 55%). ¹H NMR(400 MHz, CDCl₃): 4.38 (d, J=9.2 Hz, 1H), 3.72 (m, 1H), 3.60 (m, 1H),1.82 (m, 1H), 1.67 (m, 4h), 1.44 (s, 9H), 1.40-1.00 (m, 6H), 1.28 (d,J=6.4 Hz, 3H), 1.00-0.75 (m, 2H); MS (E/Z): 297 (M+H⁺).

Step 4. Tert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate

A solution of tert-butyl (2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate(0.215 g, 0.73 mmol) in methanol (10 mL) was added to wetted Pd/C (0.1g) and was hydrogenated with a balloon overnight. The reaction mixturewas filtered through a pad of Celite and the solvent was removed to givetert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g,78%), which was used in the next step without purification.

Step 5. Benzyl(2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate

To a mixture of tert-butyl(2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g, 0.57 mmol) andEt₃N (0.19 mL, 1.42 mmol) in methanol (5 mL) at 0° C. was added dropwisea solution of CBZCl (0.116 g, 0.68 mmol) in methanol (3 mL). The mixturewas warmed to rt, stirred 2 h, evaporated to remove methanol, dilutedwith water (15 mL) and extracted with EtOAc (3×10 mL). The combinedorganic layers were washed with brine (15 mL), dried and evaporated togive benzyl(2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate(0.117 g, 51%) that was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): 7.32 (m, 5H), 5.37 (brs, 1H),5.09 (s, 2H), 4.36 (brs (1H), 3.76 (m, 2H), 1.82 (m, 1H), 1.66 (m, 4H),1.44 (s, 9H), 1.35-1.10 (m, 6H), 1.07 (d, J=6.4 Hz, 3H), 1.00-0.78 (m,2H); MS (E/Z): 405 (M+H⁺).

Step 6. Benzyl (2S,3S)-3-amino-4-cyclohexylbutan-2-ylcarbamate

Benzyl(2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate(0.117 g, 0.29 mmol) was dissolved in 2 N HCl in methanol (10 mL, 20mmol). The mixture was allowed to stir at 40-50° C. for 2 h. The mixturewas concentrated in vacuo to give the HCl salt of benzyl(2S,3S)-3-amino-4-cyclohexylbutan-2-ylcarbamate (0.077 g, 78%).

Example 16 Benzyl (2R,3S)-3-amino-4-cyclohexylbutan-2-ylcarbamate

The procedure in Example 15 was followed starting with(1S,R)-(2-cyclohexyl-1-oxiranyl-ethyl)-carbamic acid tert-butyl ester.

Example 17 tert-Butyl (S)-1-amino-3-cyclohexylpropan-2-ylcarbamate

Step 1. (S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropylmethanesulfonate

A solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate(3.02 g, 11.7 mmole) in CH₂Cl₂ (50 mL) and triethylamine (4.0 mL, 28.6mmol) was cooled to −20° C. (internal temperature). Neat methanesulfonylchloride (2.0 mL, 25.7 mmol) was added dropwise, maintaining theinternal temperature at −20° C. (+/−5° C.). The reaction mixture wasstirred at −20° C. for an additional 30 min and at 0° C. for 1 h.Reaction progress was followed by TLC and LC-MS. The reaction wasquenched with ice-cold water, extracted with CH₂Cl₂ (3×20 mL), washedwith water (3×10 mL), dried (Na₂SO₄), decanted, and stripped to give4.13 g (quant) of product. ¹H NMR (CDCl₃) δ 0.80-1.40 (10H), 1.40 (s,9H), 1.65 (t, 2H), 1.75 (d, 1H), 2.95 (s, 3H), 3.94 (m, 1H), 4.10 (m,1H), 4.24 (m, 1H), 4.60 (m, 1H). MS ESI +ve m/z 236 (M(−BOC)+1).

Step 2. (S)-tert-Butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate

(S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate(13.3 g, 39.3 mmol) from Step 1 was dissolved in anhydrous DMF (140 mL).Solid NaN₃ (5.18 g, 79.7 mmol) was added and the reaction was warmed to50° C. for 5 h. The reaction mixture was permitted to cool to rt and thesolvent was removed under reduced pressure (150 Torr, 55° C.). Thismaterial was taken up into Et₂O (150 mL), washed with water (3×10 mL)and brine (3×10 mL), dried (Na₂SO₄), decanted, and stripped to give 13.9g crude product. This was separated on a silica column using a gradientfrom 0-100% EtOAc in hexanes. Solvent was stripped from appropriatefractions to give (S)-tert-butyl1-azido-3-cyclohexylpropan-2-ylcarbamate (7.21 g, 65%) as a clear oil.¹H NMR (CDCl₃) δ 0.60=1.80 (m 12H), 1.40 (s, 9H), 2.86 (d, 1H), 3.29 (d,1H), 4.85 (d, 1H), 4.51 (m, 1H), 8.00 (s, 1H). MS ESI +ve m/z 183(M(−BOC)+1).

Step 3. (S)-tert-Butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate

A solution of (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate(7.2 g, 25.5 mmol) in methanol (250 mL) was added to wetted Pd/C (1.0 g)in a N₂-filled Parr bottle. After 3 vac/purge cycles with H₂, the vesselwas charged to 50 psi and shaken on a Parr apparatus overnight.Theoretical equivalents (36 psi) of H₂ were consumed. The reactionmixture was filtered through a pad of Celite and the solvent was removedto give (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (5.9 g,90%) as a white solid. ¹H NMR (D6-DMSO) δ 0.70-1.30 (m 10H), 1.38 (s,9H), 1.58 (d, 2H), 1.80 (d, 1H), 2.66 (m, 1H), 2.78 (d, 1H), 3.74 (m,1H), 6.77 (d, 1H), 8.0 (bs, 2H). MS ESI +ve m/z 157 (M(−BOC)+1).

Example 18 (S)-3-Cyclohexyl-N¹,N¹-dimethylpropane-1,2-diamine

Step 1. (S)-tert-Butyl3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate

Solid EDC.HCl (4.62 g, 24.1 mmol) was added to a solution of(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (5.08 g,19.0 mmol), diisopropylethylamine (10.0 mL, 57 mmol), HOBt (0.38 g, 2.8mmol), DMAP (0.16 g, 1.3 mmol), dimethylamine (15 mL of a 2 M THFsolution, 30 mmol), and anhydrous DMF (50 mL). The resultant clear lightyellow solution was stirred at rt and the reaction progress was followedby LC-MS. After 5 h, the solvent was removed (50° C., 150 Torr). Theresidue was taken up in ether (200 mL) and washed with satd aq NaHCO₃(3×25 mL). Hexanes (100 mL) was added to the Et₂O extract and this waswashed with water (5×10 mL) and brine (3×10 mL), dried (Na₂SO₄),decanted and stripped. The crude material was purified using 40 g SiO₂with an eluent of hexanes to EtOAc. Combining appropriate fractions andremoval of solvent gave (S)-tert-butyl3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (3.85 g, 69%)as a white solid. MS ESI +ve m/z 321 (M+Na)⁺.

Step 2. (S)-tert-Butyl1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate

A 1 M solution of LiAlH₄ in THF (35 mL, 35.0 mmol) was added to asolution of (S)-tert-butyl3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (3.85 g, 12.9mmol) in THF at −78° C. at a rate to maintain the temperature below −60°C. The reaction was permitted to warm to 25° C. and conversion toproduct was monitored by LC-MS. After 6 h, the reaction was cooled to 0°C., and H₂O (3.0 mL) was added dropwise, followed by 1 N aq NaOH (3.0mL), maintaining the temperature below 10° C. Ether (100 mL) and Celite(10 g) were added to the heterogenous mixture, stirred for 30 minutesand filtered through a pad of Celite. The solvent was removed and theresidue was separated on 12 g of SiO₂ with an eluent gradient fromhexanes to 30% MeOH in EA. Appropriate fractions were combined and thesolvent was removed to afford (S)-tert-butyl1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate (0.26 g, 7%) as awhite solid. MS ESI +ve m/z 285 (M+Na)⁺.

Step 3. (S)-3-Cyclohexyl-N¹,N¹-dimethylpropane-1,2-diamine

Solid (S)-tert-butyl 1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate(263 mg, 0.97 mmol) was dissolved in 4 M HCl in dioxane (10 mL, 40 mmol)and H₂O (1 mL). After 2 h, the solvent was removed (50° C., 150 mm) andthe residual solvent was azeotroped with toluene (2×10 mL) to afford(S)-3-Cyclohexyl-N¹,N¹-dimethylpropane-1,2-diamine dihydrochloride(245.3 mg, 100%) as a white solid. MS ESI +ve m/z 185 (M(−BOC)+1)⁺.

Example 19

The following intermediates were prepared according to proceduresanalogous to those used in Example 18:

-   2-(trimethylsilyl)ethyl (S)-2-amino-4-methylpentylmethylcarbamate-   2-(trimethylsilyl)ethyl (S)-2-aminopropylmethylcarbamate.

Example 20(2S)-2-amino-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane

Step 1. (S)-tert-Butyl1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate

Solid EDC.HCl (518 mg, 3.3 mmol) was added to a solution of(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (405 mg, 1.5mmol), diisopropylethylamine (2.5 mL, 14 mmol), HOBt (130 mg, 1.0 mmol),DMAP (18 mg, 0.15 mmol), butylamine (0.30 mL, 3 mmol), and anhydrous DMF(25 mL). The resulting clear light yellow solution was stirred at rt for12 h. The solvent was removed (50° C., 150 Torr) and the residue wastaken up in ether (100 mL) and washed with satd aq NaHCO₃ (3×10 mL).Hexanes (30 mL) was added to the ether extract and this was washed withwater (5×5 mL) and brine (3×5 mL), dried (Na₂SO₄), decanted, strippedand the crude material was purified using 40 g SiO₂ with an eluent ofhexanes to 30% MeOH in EA. Combining appropriate fractions and removalof solvent gave (S)-tert-butyl1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate (417 mg, 85%) as awhite solid. ¹H NMR (CDCl₃) δ 0.80-1.80 (m 20H), 1.50 (s, 9H), 3.20 (m,2H), 4.01 (d, 1H), 5.01 (d, 1H), 6.50 (bs, 1H). MS ESI +ve m/z 321(M+Na).

Step 2.(2S)-2-(tert-Butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane

A 1 M solution of LiAlH₄ in THF (2.5 mL, 2.5 mmol) was added to asolution of (S)-tert-butyl1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate (384.7 mg, 1.18mmol) in THF (10 mL) at 0° C. The reaction was permitted to warm to 25°C. and stirred for 12 h. The reaction was cooled to 0° C., and H₂O (0.2mL) and then 1 N NaOH (0.2 mL) were introduced with cautious dropwiseaddition maintaining the temperature below 10° C. The resulting gel wasfiltered through a pad of Celite and the solids were washed with Et₂O(50 mL). The solvent was removed to yield crude(2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane(312.8 mg, 85%) as a white solid. MS ESI +ve m/z 313 (M+1). The crudeamine was used without further purification.

Step 3.(2S)-2-(tert-Butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane

Solid Teoc-OSu (390 mg, 1.5 mmol) was added to a vigorously stirred2-phase mixture of(2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane(312.8 mg, 1.0 mmol), Na₂CO₃ (525 mg, 5.0 mmol), H₂O (5.0 mL), andCH₂Cl₂ (25.0 mL). The mixture was stirred for 90 min at rt and thereaction was taken up in CH₂Cl₂ (50 mL), washed with brine (3×10 mL),dried over Na₂SO₄, decanted, and stripped to give a clear oil. This oilwas separated on a 4 g SiO₂ column to give crude(2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane(486.5 mg, 106%) as a clear oil (quant). MS ESI +ve m/z 479 (M+Na). Thecrude product was used without further purification.

Step 4.(2S)-2-amino-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane

A solution of toluenesulfonic acid monohydrate (199.4 mg, 1.0 mmol) inabsolute EtOH (1.0 mL) was added to a solution of(2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane(468.5 mg, 1.03 mmol) in Et₂O (10 mL). This solution was placed in aflask on a rotary evaporator and the Et₂O was removed at rt. The flaskwas then lowered into the water bath (temperature: 60° C.) and theselective removal of the Boc group proceeded concurrently with removalof the remainder of solvent to afford(2S)-2-amino-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane(556.7 mg, 98%) as a white solid.

Example 21

The following intermediates were prepared using procedures analogous tothose used in Example 20:

-   (2S)-1-(N-ethyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine-   (2S)-1-(N-propyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine-   (2S)-1-(N-isobutyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine-   (2S)-1-(N-isopentyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine-   (2S)-1-(N-pentyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine    and-   (S)-2-(trimethylsilyl)ethyl    2-amino-3-cyclohexylpropyl(2-methoxyethyl)carbamate.

Example 22 2-(Trimethylsilyl)ethyl(S)-3-cyclohexyl-2-(methylamino)propylcarbamate

Step 1. (2S)-tert-Butyl1-cyclohexyl-3-(N-phthalimido)propan-2-ylcarbamate

A solution of (S)-tert-butyl 1-cyclohexyl-3-hydroxypropan-2-ylcarbamate(0.992 g, 3.86 mmol), triphenylphosphine (1.502 g, 5.8 mmol), andphthalimide (0.8505 g, 5.8 mmol) in THF (40 mL) was cooled to 0° C. Neatdiisopropyl azodicarboxylate (1.15 mL, 5.94 mmol) was introduced withfast dropwise addition resulting in a persistent yellow color. Thereaction mixture was stirred 12 h at rt. Reaction progress was followedby LC-MS. The reaction solvent was removed under reduced pressure andthe crude residue was taken up in CH₂Cl₂ (50 mL) and filtered through apad of Celite. The solvent was removed and this material was separatedon 40 g SiO₂ using an eluent gradient from hexanes to EtOAc. Appropriatefractions were combined and stripped to afford (2S)-tert-butyl1-cyclohexyl-3-(N-phthalimido)propan-2-ylcarbamate (1.36 g, 92%) as awhite solid. MS ESI +ve m/z 409 (M+Na).

Step 2. (2S)-tert-Butyl1-cyclohexyl-3-(N-phthalimido)propan-2-yl(methyl)carbamate

A solution of (2S)-tert-butyl1-cyclohexyl-3-(N-phthalimido)propan-2-ylcarbamate (523.6 mg, 1.38 mmol)in anhydrous THF (10 mL) was cooled to 0° C. A 0.5 M solution ofpotassium hexamethyldisilazide in tolulene (6.0 mL, 3.0 mmol) was addedover 15 minutes. The resulting deep yellow solution was stirred for anadditional 15 minutes at 0° C. and neat methyl iodide (0.5 mL, 8.0 mmol)was added. The resulting mixture was permitted to warm to rt and stirredfor an additional 4 h. The solvent was removed under reduced pressure,dissolved in a minimal amount of CH₂Cl₂ and separated on 4 g of silicausing a gradient from hexanes to EtOAc. Solvent was stripped fromappropriate fractions to give (2S)-tert-butyl1-cyclohexyl-3-(N-phthalimido)propan-2-yl(methyl)carbamate (284 mg, 52%)as a white solid. ¹H NMR (CDCl₃) δ 0.80-1.80 (m 13H), 1.14 (s, 9H), 3.54(m, 1H), 3.68 (m, 1H), 4.63 (m, 1H), 7.67 (m, 2H), 7.79 (m, 2H). MS ESI+ve m/z 423 (M+Na).

Step 3

A solution of tert-butyl(S)-3-cyclohexyl-1-(1,3-dioxoisoindolin-2-yl)propan-2-ylmethyl-carbamate(244 mg, 0.61 mmol), hydrazine monohydrate (0.15 mL, 3.0 mmol), andabsolute ethanol (100 mL) was warmed to 50° C. for 4 h. The reaction wasthen warmed to reflux for an additional 6 h. LC-MS indicated fullconversion to the deprotected amine. The reaction mixture was cooled to25° C., suspended in Et₂O (25 mL) and filtered through a pad of Celite.Solvent was removed and the crude material (189.1 mg, theoretical: 164.7mg) was carried on to the next step directly. MS ESI +ve m/z 271 (M+1).

Step 4

Solid Teoc-OSu (23.7 mg, 1.3 mmol) was added to a vigorously stirred2-phase mixture of tert-butyl(S)-1-amino-3-cyclohexylpropan-2-ylmethylcarbamate (19.2 mg, 0.07 mmol),K₂CO₃ (500 mg, 3.6 mmol), H₂O (5.0 mL), and CH₂Cl₂ (10.0 mL). Thismixture was stirred for 90 minutes at rt and then the reaction was takenup in CH₂Cl₂ (50 mL) washed with brine (3×10 mL), dried over Na₂SO₄,decanted, and stripped to give a clear oil. This oil was separated on a4 g SiO₂ column to give 2-(trimethylsilyl)ethyl(S)-3-cyclohexyl-2-((tert-butylcarbamoyl)-methylamino)propylcarbamate(21.3 mg, 72%) as a clear oil. ¹H NMR (CDCl₃) δ 0.00 (s, 9H), 0.80-1.80(m 13H), 1.37 (s, 9H), 2.63 (s, 3H), 3.03 (m, 1H), 3.17 (m, 1H), 4.10(m, 2H), 4.2 (m, 1H). MS ESI +ve m/z 438 (M+Na).

Step 5

A solution of toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) inabsolute ethanol (1 mL) was added to a solution of2-(trimethylsilyl)ethyl(S)-3-cyclohexyl-2-((tert-butyl-carbamoyl)methylamino)propylcarbamate(21.3 mg, 0.51 mmol) in Et₂O (10 mL). This solution was placed in aflask on a rotary evaporator and the Et₂O was removed at ambient temp.The flask was then lowered into a water bath (60° C.) and selectiveremoval of the Boc group proceeded concurrently with removal of thesolvent. The reaction was complete within 2 h. This material was takenup in CH₂Cl₂ (20 mL) and 1N aq NaOH (10 mL) and extracted with CH₂Cl₂(2×10 mL). The combined organic layers were washed with brine (2×5 mL),dried over Na₂SO₄, decanted, and stripped to afford2-(trimethylsilyl)ethyl (S)-3-cyclohexyl-2-(methylamino)propylcarbamate(15.0 mg, 94%) as a clear film. MS ESI +ve m/z 315 (M+1).

Example 233-((S)-1-Amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione(I-76A)

Step 1. 3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine

tert-Butyl3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine-1-carboxylate(28.0 mg, 0.07 mmol) was dissolved in 4 N HCl in dioxane. The resultingsolution was stirred at rt until no starting material was left (˜30min). The solvent was removed in vacuo to give3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine hydrochloride asan oil. MS ESI +ve m/z 282 (M+1).

Step 2.3-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-4-methoxycyclobut-3-ene-1,2-dione

To a solution of 3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidinehydrochloride (0.07 mmol), and triethylamine (0.2 mL) in MeCN (0.8 mL)was added 3,4-dimethoxycyclobut-3-ene-1,2-dione (8.5 mg, 0.08 mmol). Themixture was stirred at rt until no starting material remained (˜10 min)and the crude3-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-4-methoxycyclobut-3-ene-1,2-dionewas used for next steps without isolation. MS ESI +ve m/z 414 (M+Na).

Step 3. tert-Butyl(2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate

To the crude3-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-4-methoxycyclobut-3-ene-1,2-dionein MeCN there was added tert-butyl(S)-2-amino-3-cyclohexylpropylcarbamate (27.0 mg, 0.11 mmol), theresulting solution was stirred at rt for 10 min, filtered through HPLCfilter, purified by HPLC to give tert-butyl(2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate(17.4 mg, 40%) as on oil. MS ESI +ve m/z 616 (M+1).

Step 4.3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione

tert-butyl(2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate(17.4 mg, 0.03 mmol) was treated with neat TFA for 30 min. TFA wasremoved in vacuo, and the residue was purified by HPLC to give3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione(8.7 mg, 60%) as a TFA salt. ¹H NMR (CD₃OD) δ 0.8-2.1 (20H), 3.0 (1H),3.1 (1H), 3.25 (s, 3H), 3.3 (m, 6H), 3.5 (2H), 4.45 (d, 1H), 4.63 (m,1H), 7.15 (1H), 7.21 (1H), 7.35 (1H), 7.40 (1 H). MS ESI +ve m/z 516(M+1).

Example 243-(1S,2S-2-Amino-1-cyclohexylmethyl-propylamino)-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dione(I-70A)

Step 1.[(2S,3S)-cyclohexyl-2-(2-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-3,4-dioxo-cyclobut-1-enylamino)-1-methyl-propyl]-carbamicacid benzyl ester

A solution of the HCl salt of(2S,3S)-(2-amino-3-cyclohexyl-1-methyl-propyl)-carbamic acid benzylester (77 mg, 0.226 mmol),3-methoxy-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dione(67.4 mg, 0.181 mmol) and triethylamine (59.5 mg, 0.452 mmol) in ethanol(10 mL) was stirred at rt until the reaction was completed (about 8-10h). The solvent was removed by evaporation and the crude productpurified by preparative HPLC to give(2S,3S)-cyclohexyl-2-(2-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-yl}-3,4-dioxo-cyclobut-1-enylamino)-1-methyl-propyl]-carbamicacid benzyl ester (5 mg, 3.5%). MS m/z 405 (M+H⁺).

Step 2.3-(1S,2S-2-amino-1-cyclohexylmethyl-propylamino)-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dione

To a solution of[(2S,3S)-cyclohexyl-2-(2-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-3,4-dioxo-cyclobut-1-enylamino)-1-methyl-propyl]-carbamicacid benzyl ester (5 mg, 0.00775 mmol) in EtOAc (5 mL) was addedpalladium hydroxide 20 wt. % on carbon (2 mg). The mixture was stirredunder a hydrogen balloon at rt overnight. The mixture was filtered andthe filtrate was evaporated to give a residue, which was purified bypreparative HPLC to give3-(1S,2S-2-amino-1-cyclohexylmethyl-propylamino)-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dione(0.6 mg, 15.1%) as a TFA salt ¹H NMR (400 MHz, CDCl₃): 7.32 (m, 5H),4.68 (m, 2H), 4.21 (m, 1H), 3.55-3.05 (m, 8H) (1H), 3.32 (s, 3H),2.05-0.75 (m, 21H), MS m/z 512 (M+H⁺).

Example 253-(1S,2R-2-Amino-1-cyclohexylmethyl-propylamino)-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dione(I-70B)

Procedures analogous to those used in Example 24 were followed to afford3-(1S,2R-2-amino-1-cyclohexylmethyl-propylamino)-4-{3-[(3-methoxy-propoxy)-phenyl-methyl]-piperidin-1-yl}-cyclobut-3-ene-1,2-dioneTFA salt. ¹H NMR (400 MHz, CDCl₃): 7.32 (m, 5H), 4.68 (m, 3H), 4.21 (m,1H), 3.55-3.10 (m, 8H), 3.32 (s, 3H), 1.95-0.80 (m, 21H). MS (E/Z): 512(M+H⁺).

Example 26

The following compounds of Formula I were prepared following proceduresanalogous to those used in Example 23, 24, and 25:

Cpd. No. Name I-58A3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-58A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-58A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-75A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(4-fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-99A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione

Example 273-((S)-1-amino-3-cyclohexyl-propan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione(I-55A)

Step 1. (S)-2-(trimethylsilyl)ethyl3-cyclohexyl-2-(2-methoxy-3,4-dioxocyclobut-1-enylamino)propylcarbamate

Solid 3,4-dimethoxycyclobut-3-ene-1,2-dione (87.5 mg, 0.61 mmol) wasadded to a solution of(S)—N¹-((2-(trimethylsilyl)ethoxy)methyl)-3-cyclohexylpropane-1,2-diamine(173.1 mg, 0.57) and triethylamine (0.2 mL, 1.4 mmol) in MeOH (10 mL).After stirring at rt for 2 h, the solvent was removed and the residuewas purified using 4 g SiO₂ with an eluent of hexanes to EtOAc. Removalof solvent from appropriate fractions yielded(S)-2-(trimethylsilyl)ethyl3-cyclohexyl-2-(2-methoxy-3,4-dioxocyclobut-1-enylamino)propylcarbamate(186.2 mg, 80%) as a clear film. MS ESI +ve m/z 433 (M+Na).

Steps 2 and 3.3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione

A solution of3-((S)-1-((2-(trimethylsilyl)ethoxy)methylamino)-3-cyclohexylpropan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione(13.4 mg, 0.034 mmol) in dry CH₃CN (0.2 mL) was added to neat3-((2-cyclopropylethoxy)(phenyl)methyl)piperidine (24.4 mg, 0.094 mmol).The mixture was stirred at rt overnight and heated to reflux for severalh until no further reaction was evident as monitored by LC-MS. Thesolvent was evaporated and purified via preparative HPLC (C-18 column,10 to 90% CH₃CN in H₂O containing 0.01% CF₃CO₂H over 10 min, 20 mL/min)to afford 2-(trimethylsilyl)ethyl(S)-2-(2-(3-((2-cyclopropylethoxy)-(phenyl)-methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)-3-cyclohexylpropylcarbamate(12.3 mg, 55%) as an oil. MS ESI +ve m/z 638 (M+1).

TheN—((S)-2-(2-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)-3-cyclohexylpropyl)-4-(trimethylsilyl)butanamide(12.3 mg, 0.02 mmol) was dissolved in dioxane (1 mL) and treated with 4MHCl in dioxane (0.5 mL, 2.0 mmol). The solution was allowed to stir for1.5 h before evaporation of solvent. The residual oil was redissolved inmethanol and evaporated under reduced pressure to afford3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dionehydrochloride as an oil (10 mg, >99%). MS ESI +ve m/z 494 (M+1).

Example 28

The following compounds of Formula I were prepared following proceduresanalogous to those used in Example 27:

Cpd. No. Name I-58A3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-58A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-59A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(2-((3-methoxypropoxy)(phenyl)methyl)morpholino)cyclobut-3-ene-1,2-dione I-69A3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-(1-hydroxy-1-phenylheptyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-71A3-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-4-(N-((S)-1-amino-3-cyclohexylpropan-2-yl)-N-methylamino)cyclobut-3-ene-1,2- dioneI-73A 3-((S)-3-cyclohexyl-1-(methylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-85A 3-(3-cyclohexyl-1-(ethylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-89A 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(2,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-90A3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(3,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-92A3-(3-cyclohexyl-1-(propylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-94A 3-(3-cyclohexyl-1-(isobutylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-95A 3-(3-(butylamino)-1-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-98A 3-(3-cyclohexyl-1-(methylamino)propan-2-ylamino)-4-(3-((3-ethoxypropoxy)(3,4-difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-101A3-(1-cyclohexyl-3-(pentylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneI-102A 3-(1-cyclohexyl-3-(isopentylamino)propan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione

Example 29(3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide(I-5A)

Step 1.(R)-3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carbonylchloride

(R)-tert-butyl3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (219mg, 0.603 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL, 80 mmol)and stirred for 30 min. LC-MS showed removal of the Boc protectinggroup. The reaction mixture was concentrated and redissolved dry CH₂Cl₂(5 mL). Pyridine (122 μL, 1.51 mmol, 2.5 equiv) was added. This solutionwas added dropwise under N₂ to a solution of triphosgene (188 mg, 0.63mmol, 1.05 equiv) in dry CH₂Cl₂ (5 mL) at −78° C. After 10 min, thereaction mixture was warmed to rt and stirred for 2 h. LC-MS showed thereaction was complete. 5% aq HCl (15 mL) was added and the layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (2×30 ml). Thecombined organic layers were washed with satd aq NaHCO₃ and brine, anddried over Na₂SO₄. Concentration afforded(R)-3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carbonylchloride (188 mg, 96%) as a yellow oil. LC-MS (3 min) t_(R)=1.83 min,m/z 344 (M+H₂O). The crude product was used for the next step withoutfurther purification.

Step 2. 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-methoxypropoxy)-(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexyl-propylcarbamate

Crude (R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carbonylchloride (60 mg, 0.184 mmol), 2-(trimethylsilyl)ethyl(S)-2-amino-3-cyclohexylpropylcarbamate (69 mg, 0.23 mmol, 1.25 equiv)and triethylamine (64 μL, 0.46 mmol, 2.5 equiv) were combined in CH₂Cl₂(1 mL) at rt and left on the shaker overnight. After concentration, theproduct was isolated by prep HPLC to afford 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-methoxypropoxy)-(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexyl-propylcarbamate(85.3 mg, 79%). LC-MS (3 min) t_(R)=2.44 min, m/z 590 (M+1).

Step 3.(3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide

2-(Trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylcarbamate(85.3 mg, 0.14 mmol) was dissolved in 6 mL 1:1 TFA/CH₂Cl₂ (6 mL) andstirred for 30 min. LC-MS showed the reaction was complete. Afterconcentration,(3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamidetrifluoroacetic acid salt was isolated by prep HPLC. LC-MS (3 min)t_(R)=1.56 min, m/z 446 (M+1). ¹H NMR (CD₃OD) δ 7.37-7.25 (m, 5H), 4.30(d, 1H), 4.03 (m, 1H), 4.97-4.90 (m, 2H), 3.50-3.39 (m, 2H), 3.27 (s,3H), 3.00 (dd, 1H), 2.85-2.75 (m, 3H), 1.81-0.82 (m, 22H).

Example 30

The following compounds of Formula I were prepared using proceduresanalogous to those used in Example 29:

Cpd. No. Name I-10A(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine- 1-carboxamideI-16A 3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-20A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-hydroxy-4-methoxy-1-phenylbutyl)piperidine- 1-carboxamide I-26A3-((3-methoxypropoxy)(3-cyanophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-30A3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide I-45A3-((3-methoxypropoxy)(3-cyanophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-c arboxamide I-47A3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(propylamino)propan-2-yl)piperidine-1-carboxamide I-49A3-((3-propoxypropoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-61A3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-(butylamino)-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-62A3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(isobutylamino)propan-2-yl)piperidine-1-carboxamide I-63A(3R)-N-((S)-3-cyclohexyl-1-(dimethylamino)propan-2-yl)-3-((R)-5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine- 1-carboxamide I-77A3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(isopentylamino)propan-2-yl)piperidine-1-carboxamide I-78A3-((3-methoxypropoxy)(phenyl)methyl)-N-(3-cyclohexyl-1-(pentylamino)propan-2-yl)piperidine-1-carboxamide

Example 31 4-Nitrophenyl(S)-3-cyclohexyl-1-((2-(trimethylsilyl)ethylcarbamate)methylamino)propan-2-yl)carbamate

A 100-mL round bottom-flask was charged with diisopropylethylamine (820mg, 6.34 mmol, 2.0 equiv), 2-(trimethylsilyl)ethyl(S)-2-amino-3-cyclohexylpropylmethylcarbamate (996 mg, 3.17 mmol, 1.0equiv) and 30 mL of CH₂Cl₂, and the resulting solution cooled to 0° C. Asolution of 4-nitrophenylchloroformate (733 mg, 3.64 mmol, 1.15 equiv)in 20 mL of CH₂Cl₂ was added at a rate such that the internaltemperature did not rise above 5° C. After 1 h an aliquot was examinedby LC-MS which showed no remaining starting material. The reaction wasquenched with water and separated. The organic layer was washed with of5% aq K₂CO₃ (2×40 mL), 0.25 M aq HCl, and brine, dried over Na₂SO₄ andevaporated. Excess 4-nitrophenyl-chloroformate was removed by flashchromatography on silica, eluting with 0 to 10% methanol in CH₂Cl₂. Thisafforded 4-nitrophenyl(S)-3-cyclohexyl-1-((2-(trimethylsilyl)ethylcarbamate)-methylamino)propan-2-yl)carbamate(990 mg, 65%). MS ESI +ve m/z 503 (M+Na⁺).

Example 32(3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-31B)

Step 1. 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate

(R)-tert-butyl3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (150 mg,0.39 mmol) was dissolved in 1:1 TFA/CH₂Cl₂ (8 mL) and stirred for 30 minat rt. LC-MS showed the Boc protecting group had been removed. Thereaction mixture was concentrated, redissolved in CH₂Cl₂ (5 mL) and Et₃N(2 mL). A solution of 4-nitrophenyl(S)-3-cyclohexyl-1-((2-(trimethylsilyl)ethylcarbamate)methylamino)propan-2-yl)carbamate(185 mg, 0.39 mmol, 1 equiv) in CH₂Cl₂ (4 mL) was added. After stirringovernight at rt, the reaction mixture was concentrated and purified byreverse phase preparative HPLC to afford 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(172.5 mg, 72%). LC-MS (3 min) t_(R)=2.64 min, m/z 618 (M+1), 640(M+Na). ¹H NMR (CDCl₃) δ 7.24 (m, 5H), 5.16 (d, 1H), 4.11-4.00 (m, 4H),3.92 (m, 1H), 3.71 (d, 1H), 3.56-3.21 (m, 7H), 3.00-2.90 (m, 1H), 2.90(s, 3H), 2.73 (t, 1H), 2.61 (m, 1H), 1.81-1.51 (m, 9H), 1.20-0.75 (m,16H), 0.01 (s, 9H). Chiral HPLC indicated 94.5% purity.

Step 2.(3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

2-(trimethylsilyl)ethyl(S)-2-((R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(172 mg, 0.28 mmol) was dissolved in acetonitrile (8 mL) andtetraethylammonium fluoride (123 mg, 0.84 mmol, 3 equiv) was added. Themixture was heated at 50° C. overnight. LC-MS showed the reaction wascomplete. The crude product was purified by reverse phase preparativeHPLC to afford(3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideas its trifluoroacetic acid salt (90 mg, 68%). LC-MS (3 min) t_(R)=1.58min, m/z 474 (M+1). ¹H NMR (CD₃OD) δ 7.38-7.23 (m, 5H), 4.29 (d, 1H),4.09 (m, 1H), 3.94 (m, 2H), 3.55-3.38 (m, 4H), 3.30 (s, 3H), 3.05 (d,1H), 2.89 (t, 1H), 2.81-2.70 (m, 2H), 2.69 (s, 3H), 1.93-0.92 (m, 24H).Chiral HPLC indicated 94.6% purity.

Example 33

The following compounds of Formula I were prepared by proceduresanalogous to those used in Example 32:

Cpd. No. Name I-3A3-((2-cyclopropylethoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-4AN-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-(5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-5C(3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-5A3-((3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-5B(3S)-3-((3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-8A2-((3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)morpholine-4-carboxamide I-13AN-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxamide I-17A3-((4-methoxybutoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-17A3-((3-ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-18AN-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-19A(3R)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-19A3-((3-methoxypropoxy)(phenyl)methyl)-N-(1-amino-3-cyclohexylpropan-2-yl)-N-methylpiperidine-1-carboxamide I-21A(3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-22A3-((3-methoxypropoxy)(4-fluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-23A3-((3-methoxypropoxy)(2-fluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-25A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(4-cyclopropyl-1-hydroxy-1-phenylbutyl)piperidine-1-carboxamide I-31A3-((3-ethoxypropoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-32A(3R)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide I-33A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-34A3-((3-ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-methylpiperidine-1-carboxamide I-35A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-4-ethoxy-1-hydroxy-1-phenylbutyl)piperidine-1-carboxamide I-39A(3R)-3-((R)-(3-methoxypropoxy)(3-fluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-40A(3R)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-41A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-41A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-42A3-((3-methoxypropoxy)(2,4-difluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-43A3-((3-methoxypropoxy)(3,4-difluorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-44A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-46A3-((3-methoxypropoxy)(2-allylphenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-48A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamide I-50A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide I-50B(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide I-53B(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-53A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-56A(3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide I-57A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(4,4,4-trifluoro-1-hydroxy-1-m-tolylbutyl)piperidine-1-carboxamide I-64A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-65A3-((3-ethoxypropoxy)(3,4-difluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-66A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-67A(3R)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-68A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-72A(3R)-3-((S)-1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-74A3-((3-methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-79A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-1-(3-isopropylphenyl)-5-methoxypentyl)piperidine-1-carboxamide I-80A(3R)-3-((R)-1-(3-chlorophenyl)-4,4,4-trifluoro-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-81A(3R)-3-((S)-1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-82A(3R)-3-(1-(3-chlorophenyl)-5-cyclopropyl-1-hydroxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-83A3-((3-methoxypropoxy)(2-phenylphenyl)methyl)-N-((S)-2-amino-3-cyclohexylpropyl)piperidine-1-carboxamide I-84A3-((3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-86B(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-86A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-88A(3R)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-91A(3R)-N-((S)-1-(carbamoylmethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-93A (3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-93A (3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-96A(3R)-3-((S)-1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide + ~10%of alcohol epimer I-97A(3R)-3-((S)-1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide + ~10% of alcoholepimer I-100A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide + ~10% of alcoholepimer I-103A(3R)-3-((S)-1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide +~10% of alcohol epimer I-104A(3R)-3-((S)-1-(5-chloro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-108A3-(1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-109A(3R)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-111AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxamide I-113A(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-116A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-117A(3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-118A(3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-120A(3R)-3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-121A(3R)-3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-123A(3R)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-124A(3R)-3-(1-hydroxy-5-methoxy-1-(2-(neopentyloxy)phenyl)pentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-130A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiazol-2-yl)pentyl)piperidine-1-carboxamide I-134A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-135A(3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-144A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-methylbenzofuran-7-yl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-145A(3R)-3-((S)-1-hydroxy-1-(2-isobutylbenzofuran-7-yl)-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-146AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)-3-methylpiperidine-1-carboxamide I-147A(3R)-3-(1-(2-(cyclopentylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-149A(3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-151A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-152A(3R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-153A(3R)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-154A(3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-159A(3R)-3-((3-methoxypropoxy)(4-chloropyridin-2-yl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-160A(R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-161A(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-162A(3R)-3-((S)-1-(2-(m-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-166A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-168A(3R)-3-((S)-1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-169A(3R)-3-((S)-1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-170A(3R)-3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-171A(3R)-3-((S)-1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-173A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,5-dimethylphenyl)pentyl)piperidine-1-carboxamide I-174A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-ethylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-175A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3-dimethylphenyl)pentyl)piperidine-1-carboxamide I-179A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-methoxyphenyl)pentyl)piperidine-1-carboxamide I-180A(3R)-3-(1-(2-(cyclopropylmethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-181A(3R)-3-(1-(3-chlorophenyl)-4-cyclopropyl-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-190A(3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-193A(3R)-3-((S)-1-(4-chloropyridin-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-194A(3R)-3-((R)-(3-ethoxypropoxy)(phenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-195A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-198A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-200A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(tetrahydro-2H-pyran-4-yl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-201A(2RS)-2-((RS)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)morpholine-4-carboxamide I-204A(R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-205A(3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-208A(3R)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-210A(3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-213A(R)-3-((S)-1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-214A(R)-3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-215A(3R)-3-((S)-1-(3-(o-tolyloxy)-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-216A(3R)-3-((S)-1-(2-(o-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-217A(3R)-3-((S)-1-(2-(5-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-218A (3R)-3-((S)-1-(2-(4-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-222A(3R)-3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-223A(3R)-3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-224A(3R)-3-((S)-1-(2-(2-chlorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-225A(3R)-3-(1-hydroxy-5-methoxy-1-(2-(neopentyloxy)phenyl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-227A(3R)-3-((S)-4-(acetylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-228A(3R)-3-(1-(2-(allyloxy)-5-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-229A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-231A(3R)-3-(4-cyclopropyl-1-hydroxy-1-(2-phenoxyphenyl)butyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-232A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(5,5,5-trifluoro-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-233A(3R)-3-(1-(3-chlorophenyl)-1,5-dimethoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-234A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide I-236A(3R)-3-(4-cyclopropyl-1-(3-fluorophenyl)-1-hydroxybutyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-240A(3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(cis-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-249A(R)-3-((S)-1-(2-(p-tolyloxy)-5-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-(2-methyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-251B(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-251A(3R)-3-(1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-254A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-(pyridin-3-yloxy)phenyl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-256A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-256B(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-263A (3R)-3-(1-(3-chlorophenyl)-5,5-difluoro-1-hydroxyhexyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-267A(3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-268A(3R)-3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-269A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-270A (3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-275A(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-276A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-277A(3R)-3-(1-(2-(benzyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-278A(3R)-3-((S)-1-(2-(m-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-279A(3R)-3-(1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-287A(3R)-3-((S)-1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-288A(3R)-3-((S)-1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-289A(3R)-3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-290A(3R)-3-((S)-1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-290B(3R)-3-((R)-1-(2-(2-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-291A(3R)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-292A(3R)-3-((S)-1-(3-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-293A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-294A(3R)-3-((R)-(3-ethoxypropoxy)(3-chlorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-299A(3R)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-300A(2RS)-2-((RS)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)morpholine-4-carboxamideI-303A(3R)-N-((S)-4,4,4-trifluoro-1-(methylamino)butan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide I-304A(3R)-3-((S)-1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-305A(3R)-N-((S)-1-(2-methoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-306A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-307A (3R)-3-((S)-1-(2-(o-tolyloxy)-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-311A(3R)-3-((S)-1-(2-(p-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-312A(3R)-3-((S)-1-(2-(o-tolyloxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-313A (3R)-3-((S)-1-(2-(5-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-314A (3R)-3-((S)-1-(2-(4-fluoro-2-methylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-315A (3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(2-(cyclopentyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-316A(3R)-3-(1-(2-(2-cyclopropylethoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-318A (3R)-3-((S)-1-(2-(4-fluorophenoxy)-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-318A (3R)-3-((R)-1-(2-(4-fluorophenoxy)-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-319A (3R)-3-((S)-1-(3,5-difluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-327A(3R)-N-((S)-1-(2-ethoxyethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-328A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-(pyridin-3-yloxy)phenyl)pentyl)piperidine-1-carboxamideI-330A(3R)-3-((S)-1-(2-(allyloxy)-3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-334A(3R)-N-(5,5,5-trifluoro-4-methyl-1-(methylamino)pentan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamideI-335A(3R)-3-(1-(2-(benzyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-337A(3R)-3-((S)-1-(2-(4-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-338A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-339A (3R)-3-((S)-1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-350A(R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-356A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methoxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-361A(R)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-374A(R)-3-((S)-1-(benzofuran-4-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-378A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methoxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-380A(R)-3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-387A(R)-3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-388A(R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-390A(R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamideI-404A2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide I-406A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamideI-406B(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamideI-408A(R)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-411A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-413A(RS)-2-((RS)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamideI-416A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-propionamidobutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-418A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(3-methylureido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-426A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1,5-dimethoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-437A(R)-2-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)morpholine-4-carboxamideI-438A(R)-3-((S)-1-(3-chlorophenyl)-4-(cyclopropanecarboxamido)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-439A(R)-3-((S)-4-butyramido-1-(3-chlorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-440A(R)-3-((S)-1-(3-chlorophenyl)-4-(3,3-dimethylureido)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-442A (R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-449A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(methylsulfonamido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-450A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(sulfamoylamino)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-451A(R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-((S)-1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-455A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-((R)-2-methoxypropanamido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-455B(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-((S)-2-methoxypropanamido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-459A(R)-3-((S)-1-(2-bromo-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-464A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-4-(2,2,2-trifluoroacetamido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-470A (3S)-3-(1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-471A(R)-2-((S)-(3-chloro-2-fluorophenyl)(3-methoxypropoxy)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide I-479A(3R)-3-((S)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1-carboxamideI-478A(3R)-3-(1-(3-chloro-2-fluorophenyl)-1-fluoro-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-502A(3R)-3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-505A(3R)-N-((2S)-1-amino-3-(tetrahydrofuran-2-yl)propan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-509A(3R)-N-((2S)-1-amino-3-(tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-510A(3R)-N-((S)-1-amino-3-(3-methoxycyclobutyl)propan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-514A(3R)-N-((2S)-1-amino-3-(tetrahydrofuran-2-yl)propan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-522A (S)-3-((R)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-522B(S)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-524A(3R)-3-((R)-(3-chloro-2-fluorophenyl)(3-methoxypropoxy)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-526A(3R)-N-((2S)-1-amino-3-(tetrahydro-2H-pyran-2-yl)propan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-528A(3R)-N-((S)-1-amino-3-(3-methoxycyclobutyl)propan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

The following compounds were prepared using procedures analogous tothose described in Example 32 Step 1 followed by acid catalyzed removalof a Boc protecting group following the conditions described in Example126, Step 2:

Cpd. No. Name I-163A(3R)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-220A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-221A(3R)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-273A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-325A(3R)-N-(3-(3,3-difluorocyclobutyl)-1-(methylamino)propan-2-yl)-3-((R)-1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)piperidine-1-carboxamide I-369A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide I-468A(3R)-N-(1-(3,3-difluorocyclobutyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-hydroxypropan-2-yl)piperidine-1-carboxamide(I-158A) was prepared by applying analogous procedures to thosedescribed in Example 32 Step 1 to (S)-4-nitrophenyl1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-ylcarbamate and(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol toafford(R)—N—((S)-1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamidefollowed by removal of the t-butyldimethylsilyl group with aqueous acid.

Example 34N2-((Z)-1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine(I-52A)

Step 1. tert-butyl(S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate

3-((3-Methoxypropoxy)(phenyl)methyl)piperidine hydrochloride (177 mg,0.59 mmol), 1,1-bis(methylthio)-2-nitroethene (117 mg, 0.71 mmol, 1.2equiv), and diisopropylethylamine (500 μL, 2.8 mmol, 5 equiv) weredissolved in acetonitrile (5 mL) and put on a shaker for 2 h. LC-MSindicated the presence of3-((3-methoxypropoxy)(phenyl)methyl)-1-((Z)-1-(methylthio)-2-nitrovinyl)piperidine.Tert-butyl (S)-2-amino-3-cyclohexylpropylcarbamate (˜300 mg, 1.17 mmol,2 equiv) was added to the mixture and shaking was continued overnight.The mixture was concentrated and purified by prep HPLC to affordtert-butyl(S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate(22 mg, 6.6%). LC-MS (3 min) t_(R)=1.92 min. m/z 589 (M+1).

Step 2.(2S)—N²-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine

Tert-butyl(S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate(12 mg, 0.02 mmol) was dissolved in 1:1 TFA/CH₂Cl₂ (3 mL) and stirredfor 30 min at rt. LC-MS showed the reaction was complete. Afterconcentration, the mixture was purified by prep HPLC to afford(2S)—N²-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine(12.4 mg, 68%). LC-MS (3 min) t_(R)=1.38 min. m/z 489 (M+1).

Example 35(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide(I-27A)

Step 1

2-(Trimethylsilyl)ethyl(S)-2-((R)-3-(5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(310 mg, 0.49 mmol) was dissolved in neat TFA (2 mL). The resultingsolution was stirred at rt until no starting material remained (˜1 h).TFA was removed in vacuo to give a mixture ofN—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((E)-5-ethoxy-1-phenylpent-1-enyl)piperidine-1-carboxamideand(Z)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentylidene)-piperidine-1-carboxamideas an oil, which was used in the next step without purification. MS ESI+ve m/z 470 (M+1).

Step 2.N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide

To a solution of above mixture in methanol (5 mL), there was added 10%Pd—C (wet, excess). The resulting suspension was stirred under aH₂-balloon at rt overnight. The mixture was filtered through Celite andthe solvent was removed under reduced pressure to giveN—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide(194.4 mg, 84%) as an oil. MS ESI +ve m/z 472 (M+1).

Step 3. tert-butyl(S)-2-((S)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl-methylcarbamate

To the solution ofN—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamidein acetone (3 mL) was added 5% aqueous K₂CO₃ (2 mL), followed by excess(Boc)₂O. The resulting solution was stirred at rt for 10 min, acetonewas removed, and the aqueous layer was extracted with ether (4×5 mL).The combined organic layers was washed with water (5 mL), brine (2 mL),dried over Na₂SO₄, and upon removal of solvent, the residue was purifiedby chiral HPLC to give tert-butyl(S)-2-((S)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl-methylcarbamate(40.7 mg, 17%) as an oil. MS ESI +ve m/z 572 (M+1).

Step 4.(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)-piperidine-1-carboxamide

tert-butyl(S)-2-((S)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(40.7 mg, 0.071 mmol) was stirred in HCl/dioxane (4 N, 4 mL) at rt untilno starting material remained. The solvent was removed to to give(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)-piperidine-1-carboxamide(32.9 mg, 91%) as its HCl salt. ¹H NMR (CD₃OD) δ 0.9 (m, 3H), 1.0 (m,2H), 1.11 (t, 3H), 1.2-2.0 (20H), 2.40 (m, 1H), 2.65 (m, 1H), 2.70 (s,3H), 3.93 (m, 1H), 3.05 (m, 2H), 3.31 (m, 1H), 3.40 (q, 2H), 3.91 (d,1H), 4.13 (m, 2H), 7.13 (2H), 7.19 (1H), 7.28 (2H). MS ESI +ve m/z 472(M+1).

Example 36(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(I-14A)

Step 1. 2-(trimethylsilyl)ethyl(S)-2-((S)-3-((R)-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate

A 100-mL round bottom flask was charged with of 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl-methylcarbamate(0.9806 g, 1.59 mol, 1.0 equiv), absolute ethanol (6 mL), and Raneynickel (2.15 g, ca. 20 equiv) (Aldrich Raney® 2800 nickel, slurry inwater, washed with distilled water prior to use until the washings wereneutral, then washed three times with absolute ethanol and stored underethanol until needed.) The reaction mixture was heated to 100° C. for 3h and then stirred at rt overnight. LC-MS showed about 60% conversion.The ethanolic solution was decanted from the catalyst. The catalyst waswashed with absolute ethanol three times, the solvent being removed bydecanting in each case. The organic solutions were combined andconcentrated in vacuo. The residue was purified by reversed-phase HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOHover 16 min, flow rate 25 mL/min) to give of 2-(trimethylsilyl)ethyl(S)-2-((S)-3-((R)-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(0.5422 g, 57%). LC-MS (3 min) t_(R)=2.61 min, m/z 624 (M+Na⁺), 602(M+H⁺). ¹H NMR (400 MHz, CDCl₃) δ 8.28 (br s, 2H), 7.29-7.25 (m, 2H),7.21-7.17 (m, 1H), 7.09-7.06 (m, 2H), 5.46 (m, 1H), 4.21-4.06 (m, 4H),3.68-3.59 (m, 2H), 3.33-3.27 (m, 2H), 3.28 (s, 3H), 2.92 (s, 3H),2.68-2.63 (m, 1H), 2.43-2.29 (m, 2H), 1.80-0.83 (m, 25H), 0.02 (s, 9H);¹³C NMR (100 MHz, CDCl₃) δ 158.5, 158.0, 142.8, 128.4, 128.2, 126.2,72.7, 64.3, 58.3, 52.8, 49.4, 49.1, 47.9, 45.1, 41.2, 41.1, 34.7, 34.3,33.4, 33.3, 32.4, 29.2, 28.7, 26.4, 26.2, 26.1, 25.1, 24.1, 17.7, −1.5.

Unconsumed starting material (0.3570 g, 36%) was recovered as well.LC-MS (3 min) t_(R)=2.40 min, m/z 640 (M+Na⁺), 618 (M+H⁺). ¹H NMR (400MHz, CDCl₃) δ 7.35-7.20 (m, 5H), 5.31 (m, 1H), 5.11 (br s, 1H), 4.30(dm, J=13.2 Hz, 1H), 4.18-4.04 (m, 3H), 3.69-3.58 (m, 2H), 3.31-3.25 (m,2H), 3.26 (s, 3H), 2.97-2.91 (m, 1H), 2.90 (s, 3H), 2.63-2.49 (m, 2H),2.03-0.84 (m, 26H), −0.01 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 158.3,157.7, 144.2, 127.9, 126.3, 125.6, 77.8, 72.5, 63.8, 58.4, 52.6, 47.7,46.1, 45.1, 44.9, 41.3, 39.0, 34.6, 34.4, 33.4, 33.3, 29.5, 26.4, 26.2,26.1, 25.4, 25.2, 20.1, 17.6, −1.5.

Step 2.(3S)—N—((S)-3-cyclohexyl-1-(methylamino)-propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide

A 100 mL round bottom flask was charged with 2-(trimethylsilyl)ethyl(S)-2-((S)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate(0.5420 g, 0.90 mmol) and trifluoroacetic acid (8 mL). The reactionmixture was stirred at rt for 2 h. The solvent was removed in vacuo andthe residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μC18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 13 min, flow rate 25 mL/min) to give the trifluoroacetate salt of(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide,which was treated with 1 N NaOH (1.5 mL), extracted with CH₂Cl₂, driedover K₂CO₃, filtered and then concentrated in vacuo. The residue wasdissolved into Et₂O and the solution was filtered through HPLC filter.The filtrate was concentrated in vacuo to give(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(0.3342 g, 81%) as an oil. LC-MS (3 min) t_(R)=1.63 min, m/z 458 (M+H⁺),262. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.25 (m, 2H), 7.21-7.16 (m, 1H),7.09-7.07 (m, 2H), 4.60 (d, J=7.9 Hz, 1H), 4.18 (dm, J=12.9 Hz, 1H),4.03-3.98 (m, 1H), 3.71 (dm, J=12.3 Hz, 1H), 3.26 (s, 3H), 3.28-3.22 (m,2H), 2.70-2.61 (m, 3H), 2.44 (t, J=12.0 Hz, 1H), 2.43 (s, 3H), 2.36-2.30(m, 1H), 1.86-0.86 (m, 25H); ¹³C NMR (100 MHz, CDCl₃) δ 157.6, 143.2,128.4, 128.2, 126.1, 72.6, 58.4, 56.4, 49.5, 48.9, 47.5, 45.0, 41.3,41.2, 36.6, 34.6, 33.7, 33.1, 32.6, 29.6, 29.1, 26.5, 26.32, 26.25,25.2, 24.2.

A solution of(3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(0.3342 g, 0.73 mmol, 1.0 equiv), obtained as described above, inmethanol was added to a solution of fumaric acid (0.0398 g, 0.34 mmol,0.47 equiv) in methanol. The methanol solvent was then removed in vacuo.The residue was dried under high vacuum. The resulting white solid waswashed twice with Et₂O to remove excess free base to afford 0.3194 g(90%) fumarate salt of(3S)—N—((S)-3-cyclohexyl-1-(methylamino)-propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide.¹H NMR (400 MHz, CD₃OD) δ 7.18-7.14 (m, 2H), 7.08-7.04 (m, 1H),7.02-6.99 (m, 2H), 6.53 (s, 1H), 4.07-4.01 (m, 2H), 3.78 (br d, J=12.9Hz, 1H), 3.15 (t, J=6.6 Hz, 1H), 3.12 (s, 3H), 2.94-2.82 (m, 2H), 2.57(s, 3H), 2.61-2.49 (m, 2H), 2.29-2.23 (m, 1H), 1.82-0.74 (m, 25H); ¹³CNMR (100 MHz, CD₃OD) δ 174.2, 159.5, 144.3, 137.1, 129.4, 129.3, 127.2,73.6, 58.6, 55.1, 50.3, 50.1, 46.7, 45.8, 42.7, 41.0, 35.4, 34.8, 33.8,33.4, 30.5, 30.0, 27.52, 27.47, 27.3, 26.1, 25.3.

Example 37

The following compounds of Formula I were prepared using proceduresanalogous to those described in Examples 35:

Cpd. No. Name I-14AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-15A(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-27AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide I-27A(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamide I-37A(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-(3-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide I-110AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-(thiophen-2-yl)pentyl)piperidine-1-carboxamide I-148A(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-(2-fluoro-5-methylphenyl)-5-methoxypentyl)piperidine-1-carboxamide I-342A(SR)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-2-((RS)-5-methoxy-1-phenylpentyl)morpholine-4-carboxamide

Example 38

The following compounds of Formula I were prepared using proceduresanalogous to those described in Examples 36:

Cpd. No. Name I-24A(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-cyclohexyl-5-methoxypentyl)piperidine-1-carboxamide I-24B(3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-cyclohexyl-5-methoxypentyl)piperidine-1-carboxamide

Example 394-(3-((2-methoxyethoxy)(phenyl)methyl)piperidin-1-yl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)-1,2,5-thiadiazol-3-amine(I-60A)

Step 1. 2-(trimethylsilyl)-ethyl(S)-2-(4-methoxy-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamate

To a stirred, ice-cold solution of 3,4-dimethoxy-1,2,5-thiadiazole1-oxide (219 mg, 1.35 mmol) (prepared as described in U.S. Pat. No.4,374,248) in methanol (40 mL) was added a solution of2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylcarbamate (406 mg,1.35 mmol) in methanol (5 mL). The ice bath was allowed to melt and themixture was stirred at rt for 2 days. The mixture was evaporated todryness under reduced pressure to afford a syrup (577 mg). The crudeproduct was triturated with methanol (5 mL) to afford2-(trimethylsilyl)-ethyl(S)-2-(4-methoxy-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamateas a sticky solid (547 mg, 94%) which was used without furtherpurification. ¹H NMR (CD₃OD) δ 0.03 (s, 9H), 0.8-1.9 (15H), 3.0-3.4(3H), 4.08 (m, 2H), 4.15 (s, 3H).

Step 2. 2-(trimethylsilyl)ethyl(S)-2-(4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamate

To a solution of 2-(trimethylsilyl)ethyl(S)-2-(4-methoxy-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamate(547 mg, 1.27 mmol) in methanol (5 mL) was added a solution of3-((2-methoxypropoxy)(phenyl)methyl)piperidine (360 mg, 1.39 mmol) inmethanol (5 mL). The mixture was stirred at rt for 3 days and thesolvent was removed under reduced pressure. The residue was taken up inEtOAc (100 mL), washed with 5% aq HCl (2×50 mL) and satd aq NaHCO₃ (50mL), and dried over MgSO₄. Removal of the solvent afforded crude productas a yellow solid (465 mg, 51%).

A 100 mg portion of crude product was applied to a 2-g silica cartridgeand eluted sequentially with 0, 10, 25, 50, 75, and 100% EtOAc inhexanes (15 mL of each) to afford six fractions. Fractions 3 and 4 werecombined and evaporated to give 2-(trimethylsilyl)ethyl(S)-2-(4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamateas an oil. ¹H NMR (CDCl₃) δ 0.03 (s, 9H), 0.8-1.9 (22H), 2.8-3.5 (11H),3.30 (s, 3H), 4.0-4.2 (5H), 7.2-7.4 (5H). MS ESI +ve m/z 662 (M+1).

Step 3.4-(3-((2-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)-1,2,5-thiadiazol-3-amine

A stirred solution of 2-(trimethylsilyl)ethyl(S)-2-(4-(3-((2-methoxypropoxy)(phenyl)-methyl)piperidin-1-yl)-1-oxo-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamate(51 mg, 0.077 mmol),bis[4-(1H,1H,2H,2H-perfluorooctyl)phenyl]phenylphosphine (101 mg, 0.078mmol), Re(PPh₃)₂OCl₃ (7 mg, 0.008 mmol), and 1,2-dichloroethane (2 mL)was heated at 100° C. for 10 min in a microwave. The mixture wasevaporated to dryness, taken up in methanol (1 mL) and applied to a 2-gfluorous SPE cartridge that had been prewetted with 20% water inmethanol. The cartridge was eluted with 20% water in methanol (15 mL)and the eluate was evaporated to afford an oil (41 mg) which was appliedto a 2 g silica SPE cartridge and eluted sequentially with 0, 10, 25,50, 75, and 100% EtOAc in hexanes (15 mL of each) to afford sixfractions. Fractions 3 and 4 were combined and evaporated to give2-(trimethylsilyl)ethyl(S)-2-(4-(3-((2-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-1,2,5-thiadiazol-3-ylamino)-3-cyclohexylpropylcarbamateas an oil (18 mg). This material was dissolved in CH₂Cl₂ (0.5 mL) andCF₃CO₂H (0.5 mL) was added. The mixture was stirred at rt for 1.5 h andevaporated under reduced pressure to leave an oil (24 mg) which wassubmitted to preparative HPLC (C-18 column, 10 to 90% CH₃CN in H₂Ocontaining 0.01% CF₃CO₂H over 10 min, 20 mL/min) to afford4-(3-((2-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)-1,2,5-thiadiazol-3-amineas its trifluoroacetic acid salt (6.8 mg, 14%) as an oil. ¹H NMR (CD₃OD)δ 0.8-1.9 (18H), 2.1 (2H), 2.5-3.5 (10H), 3.3 (s, 3H), 3.8-4.3 (3H),7.2-7.4 (5H). MS ESI +ve m/z 502 (M+1).

Example 40N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)cyclohexanecarboxamide(I-28A)

Step 1. cis-3-benzoylcyclohexane-1-carboxylic acid

A stirred solution of 1,3-cyclohexanedicarboxylic anhydride (67 mg, 0.43mmol) (prepared from 1,3-cyclohexanedicarboxylic acid as described inpatent application US 2004010005) and copper(I) iodide (8 mg, 0.04 mmol)in dry THF (3 mL) was cooled to −70° C. and phenmagnesium bromide in THF(0.4 mL of 1 M, 0.40 mmol) was added dropwise over 2 min. The mixturewas stirred at −70° C. for 1 h and allowed to warm slowly to rt. After 2h the mixture was poured into ether (75 mL) and extracted with satdaqueous NaHCO₃ (2×30 mL). The combined aqueous extracts were acidifiedto pH 1 by cautious addition of concentrated HCl and back extracted withether (2×50 mL). These ether extracts were combined, dried over Na₂SO₄and evaporated under reduced pressure to affordcis-3-benzoylcyclohexane-1-carboxylic acid (78 mg, 77%) as an oil whichsolidified on standing. ¹H NMR (CDCl₃) δ 1.3-2.8 (9H), 3.32 (m, 1H),7.45 (m, 2H), 7.55 (1=m, 1H), 7.92 (m, 2H). MS ESI +ve m/z 233 (M+1).

Step 2. 2-(Trimethylsilyl)ethyl(S)-2-(3-benzoylcyclohexane-carboxamido)-3-cyclohexylpropylmethylcarbamate

To a stirred solution of cis-3-benzoylcyclohexane-1-carboxylic acid (78mg, 0.34 mmol), 2-(trimethylsilyl)ethyl(S)-2-amino-3-cyclohexylpropylcarbamate (116 mg, 0.37 mmol) anddiisopropylethylamine (0.13 mL, 0.70 mmol) in CH₂Cl₂ (2 mL) were addedsolid 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 200 mg, 0.53 mmol) and DMF (0.5 mL). Themixture was stirred at rt for 3 h, diluted with ether (90 mL), washedwith 5% aqueous HCl (25 mL), sat'd aqueous NaHCO₃ (25 mL), and brine (25mL) and dried over Na₂SO₄. Removal of the solvent under reduced pressureleft an oil (260 mg) which was applied to a 2-g silica SPE cartridge andeluted sequentially with 0, 10, 25, 50, 75, and 100% EtOAc in hexanes(15 mL of each) to give six fractions. Fractions 2-4 were pooled andevaporated to afford 2-(trimethylsilyl)ethyl(S)-2-(3-benzoylcyclohexane-carboxamido)-3-cyclohexylpropylmethylcarbamate(170 mg, 91%) as an oil. MS ESI +ve m/z 528 (M+1).

Step 3 2-(trimethylsilyl)ethyl(S)-2-(3-(1-hydroxy-5-methoxy-1-phenylpentyl)cyclohexanecarboxamido)-3-cyclohexylpropyl-methylcarbamate

A stirred solution of 2-(trimethylsilyl)ethyl(S)-2-(3-benzoylcyclohexanecarboxamido)-3-cyclohexylpropylmethylcarbamate(111 mg, 0.21 mmol) in dry THF (2 mL) was cooled to −70° C. andmethoxybutylmagnesium chloride in THF (0.5 mL of 2 M, 1.0 mmol) wasadded dropwise over 2 min. The cooling bath was allowed to expire andthe mixture was stirred as it warmed to rt. After 2 h, the mixture waspoured into sat'd aqueous NaHCO₃ (20 mL) and sat'd aqueous NH₄Cl (20 mL)was added. The mixture was extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with brine (15 mL), dried over Na₂SO₄ andevaporated under reduced pressure to leave crude 2-(trimethylsilyl)ethyl(S)-2-(3-(1-hydroxy-5-methoxy-1-phenylpentyl)cyclohexanecarboxamido)-3-cyclohexylpropyl-methylcarbamateas an oil (124 mg, 95%). MS ESI +ve m/z 617 (M+1).

Step 4.N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)-cyclohexane-carboxamide

A solution of 2-(trimethylsilyl)ethyl(S)-2-(3-(1-hydroxy-5-methoxy-1-phenylpentyl)-cyclohexanecarboxamido)-3-cyclohexylpropylmethylcarbamate(62 mg, 0.10 mmol) and tetraethylammonium fluoride (80 mg, 0.50 mmol) inacetonitrile (2 mL) was heated at 100° C. for 10 min in a microwave. Themixture was directly submitted to preparative HPLC (C-18 column, 10 to90% CH₃CN in H₂O containing 0.01% CF₃CO₂H over 10 min, 20 mL/min) toaffordN—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)-cyclohexane-carboxamideas its trifluoroacetic acid salt (28 mg, 48%) as an oil. ¹H NMR (CD₃OD)δ 0.8-2.3 (29H), 2.62 (s, 3H), 2.8-3.1 (2H), 3.25 (s, 3H), 3.30 (m, 2H),4.1-4.3 (1H), 7.15 (1H), 7.25 (2H), 7.35 (2H), 8.8 (1H). MS ESI +ve m/z473 (M+1).

Example 41 3-((3-Methoxypropoxy)(phenyl)methyl)benzoic acid

Step 1. Ethyl 3-benzoylbenzoate

A 100-mL round bottom flask was charged with of 3-benzoylbenzoic acid(2.20 g, 9.7 mmol), ethanol (40 mL), and sulfuric acid (3 mL). Thereaction mixture was heated at 100° C. for 15 h, poured into ice waterand extracted twice with Et₂O. The combined organic phase was washedwith satd aq NaHCO₃ and dried over K₂CO₃. The crude ethyl3-benzoylbenzoate was used in the next step without furtherpurification. LC-MS (3 min) t_(R)=1.87 min in 3 min chromatography, m/z255 (MH⁺). ¹H NMR (400 MHz, CDCl₃) δ 8.45-8.44 (m, 1H), 8.28-8.25 (m,1H), 8.00-7.97 (m, 1H), 7.82-7.79 (m, 2H), 7.64-7.48 (m, 4H), 4.40 (q,J=7.1 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

Step 2. Ethyl 3-(hydroxy(phenyl)methyl)benzoate

To a solution of ethyl 3-benzoylbenzoate (1.0197 g, 4.0 mmol, 1.0 equiv)in ethanol (10 mL) was added of NaBH₄ (0.32 g, 2.1 equiv). The reactionmixture was stirred at rt for 1.5 h, quenched with 10% aq Na₂CO₃,extracted three times with CH₂Cl₂, and dried over Na₂SO₄. The crudeproduct was used in the next step without further purification. LC-MS (3min) t_(R)=1.64 min, m/z 239 (M⁺-OH). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (m,1H), 7.93-7.96 (m, 1H), 7.56-7.59 (m, 1H), 7.26-7.43 (m, 6H), 5.89 (s,1H), 4.36 (q, J=7.2 Hz, 2H), 2.38 (br s, 1H), 1.40 (t, J=7.2 Hz, 3H).

Step 3. 3-((3-Methoxypropoxy)-(phenyl)methyl)benzoic acid

To a mixture of ethyl 3-(hydroxy)(phenyl)methyl)benzoate (1.0202 g, 3.98mmol), 60% NaH in mineral oil (1.50 g, 37.5 mmol) and THF (20 mL) wasadded of 3-methoxypropyl methanesulfonate (3.00 g, 17.8 mmol). Thereaction mixture was heated at 70° C. for 16 h, quenched with water,extracted twice with EtOAc, and dried over Na₂SO₄. After solvents wereremoved in vacuo, 4.20 g of KOH (4.20 g) and ethanol (25 mL) were addedto 1.050 g of the residue. The reaction mixture was heated at 100° C.for 15 h and then the solvent ethanol was removed in vacuo. The residuewas treated with water and extracted twice with Et₂O. The aqueous phasewas treated with 2N aq HCl (60 mL), extracted twice with CH₂Cl₂ anddried over Na₂SO₄. Removal of the solvent afforded crude3-((3-methoxypropoxy)-(phenyl)methyl)benzoic acid (0.255 g), which wasused in the next step without further purification. LC-MS t_(R)=1.63 minin 3 min chromatography, m/z 421, 211 (M⁺-OCH₂CH₂CH₂OCH₃). ¹H NMR (400MHz, CDCl₃) δ 8.10 (m, 1H), 7.99 (dm, J=7.6 Hz, 1H), 7.59 (dm, J=7.6 Hz,1H), 7.42 (t, J=7.7 Hz, 1H), 7.36-7.23 (m, 5H), 5.40 (s, 1H), 3.57-3.50(m, 4H), 3.33 (s, 3H), 1.93 (p, J=6.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃)δ 171.9, 143.2, 141.8, 132.2, 129.4, 129.2, 128.63, 128.60, 128.5,127.7, 126.9, 83.2, 69.7, 66.1, 58.6, 30.0.

Example 42

The compounds listed below were prepared following procedures analogousto those described in Example 40 Step 2 followed by Step 4:

Cpd. No. Name I-2A3-((3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)benzamide I-11A3-((3-methoxypropoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide I-105AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((pent-4-enyloxy)(phenyl)methyl)benzamide I-107A3-((2-ethoxyethoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide I-115A3-((3-ethoxypropoxy)(phenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide

Example 43(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-fluoro-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(I-38A)

Step 1. 2-(trimethylsilyl)ethyl(S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate

To a 50 mL round bottom flask were added 0.0597 g (0.097 mmol, 1.0equiv) of 2-(trimethylsilyl)ethyl(S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamateand 5 mL of CH₂Cl₂. The flask was evacuated and refilled with N₂. Themixture was cooled with a dry ice-acetone bath and 0.1860 g (ca. 10equiv) of (diethylamino)sulfur trifluoride (DAST) was added. After 5min, the dry ice-acetone bath was replaced by an ice-MeOH bath (−10°C.). After an additional hour, the reaction mixture was quenched with10% Na₂CO₃ (10 mL), extracted three times with Et₂O, and dried overNa₂SO₄. The crude product was purified by reversed-phase HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOHover 15 min, flow rate 25 mL/min) to give 0.0478 g (80%) of2-(trimethylsilyl)ethyl(S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate.LC-MS t_(R)=2.59 min in 3 min chromatography, m/z 642 (M+Na⁺), 620(M+H⁺). ¹H NMR (400 MHz, CDCl₃) δ 8.83 (br s, 1H), 7.36-7.19 (m, 5H),5.42 (br s, 0.69H), 5.00 (br s, 0.31; H), 4.39-4.36 (m, 1H), 4.14-4.03(m, 3H), 3.72-3.46 (m, 2H), 3.28-3.24 (m, 5H), 2.94-2.86 (m, 4H),2.62-2.40 (m, 2H), 2.11-0.81 (m, 25H), 0.03 and −0.01 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 158.4, 157.8, 141.3, 141.0, 128.2, 128.1, 127.3,126.9, 124.7, 124.6, 101.3, 99.5, 72.52, 72.46, 63.9, 63.8, 58.4, 58.3,52.7, 52.6, 47.9, 47.6, 45.0, 44.82, 44.77, 44.6, 41.3, 41.1, 37.1,36.9, 34.7, 34.6, 34.4, 34.3, 33.5, 33.4, 33.2, 29.6, 29.5, 26.4, 26.2,26.13, 26.09, 25.1, 25.0, 24.6, 19.8, 17.7, −1.6.

Step 2.(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-fluoro-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide

A 50 mL round bottom flask was charged with 2-(trimethylsilyl)ethyl(S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethyl-carbamate(0.0453 g, 0.073 mmol), 0.3786 g of tetraethylammonium fluoride, and 5mL of acetonitrile. The reaction mixture was stirred at 80° C. for 16 h.The solvent was removed in vacuo and then purified by reversed-phaseHPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min, flow rate 25 mL/min) to give 0.0325g (75%) of trifluoroacetate salt of(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-fluoro-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide.LC-MS t_(R)=1.64 min in 3 min chromatography, m/z 476 (MH⁺), 280, 260.¹H NMR (400 MHz, CDCl₃) δ 7.29-7.15 (m, 5H), 4.23 (dm, J=13.2 Hz, 1H),4.05-3.92 (m, 1H), 3.86 and 3.71 (dm, J=13.2 Hz, 1H), 3.20-3.15 (m, 1H),3.13 (s, 3H), 3.00-2.73 (m, 2H), 2.59 and 2.55 (s, 3H), 2.51-2.39 (m,2H), 2.08-0.74 (m, 25H). Chiral HPLC indicated a mixture of two isomers(72:28).

Example 44 tert(3R)—N—((S)-1-Amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(I-12A)

Step 1. (S)-1-azido-3-phenylpropan-2-amine

A solution of tert-butyl (S)-3-azido-1-phenylpropan-2-ylcarbamate(1.0045 g, 3.6 mmol) was dissolved in 4 M HCl in dioxane (20 mL, 80mmol) and stirred at rt for 2 h. The solvent was stripped. The residuewas taken up in CH₂Cl₂ (50 mL) and 1 N aq NaOH (10 mL), extracted withCH₂Cl₂ (3×10 mL), washed with brine (3×5 mL), dried (Na₂SO₄), decanted,and stripped to afford (S)-1-azido-3-phenylpropan-2-amine (812.9 mg,quant, 80% purity) as a clear oil. MS ESI +ve m/z 177 (M+1).

Step 2.(R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonylchloride

A solution of (S)-5-methoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol(455.6 mg, 1.8 mmol) and triethylamine (1.50 mL, 10.7 mmol) in CH₂Cl₂(100 mL) was cooled to 0° C. A solution of triphosgene (278.6 mg, 1.0mmol) in CH₂Cl₂ (10 mL) was added with fast dropwise addition. Thesolution was stirred for 30 min at 0° C. and then for 2 h at rt. Thereaction mixture was cooled to 0° C., washed with ice-cold satd aqNaHCO₃ (3×10 mL) and ice-cold brine (3×10 mL), dried (Na₂SO₄), decanted,and siripped to afford(R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonylchloride (540.8 mg, 99%) as a yellow oil. This material was carried ondirectly to the next step.

Step 3.(3R)—N—((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide

A solution of(R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonylchloride (135 mg, 0.4 mmol) in CH₂Cl₂ (10 mL) was added to a solution of(S)-1-azido-3-phenylpropan-2-amine (156.3 mg, 0.73 mmol), triethylamine(0.6 mL, 4.3 mmol), and DMAP (16.6 mg, 0.13 mmol) in CH₂Cl₂. Afterstirring for 12 h, the reaction was taken up in CH₂Cl₂ (50 mL), washedwith satd aq NaHCO3 (3×10 mL), and brine (3×10 mL), dried (Na₂SO₄),decanted, and stripped to afford(3R)—N—((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(210.7 mg) as a brown residue (theoretical yield: 192.0 mg). MS ESI +vem/z 502 (M+Na).

Step 4.(3R)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide

Crude(3R)—N—((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(210.7 mg, 91% purity, 0.4 mmol) from the previous step was dissolved inMeOH (10 mL) and was added to 0.2 g of Pd/C previously wetted with adrop of H₂O. After 3 vacuum/purge cycles using 12 torr vacuum and 14 psiH₂, the reaction was stirred under an atmosphere of H₂ at 14 psi for 30minutes. The crude mixture was filtered through a plug of Celite and thesolvent was removed. The resulting oil was dissolved in a minimal volumeof 1:1 acetonitrile:H₂O then separated by prep HPLC on a C-18 columnusing a gradient of 0.05% TFA in H₂O and acetonitrile. Appropriatefractions were combined, made slightly basic with 1 N NaOH, and thesolvent was removed at 50° C. and 150 torr. The residue was taken up inCH₂Cl₂ (50 mL) and 1 N NaOH (10 mL). The organic layer was dried(Na₂SO₄), decanted and stripped to afford(3R)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide(61.5 mg, 34% overall yield from(R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonylchloride) as a clear colorless film. MS ESI +ve m/z 454 (M+1).

Example 45

The following compounds of Formula I were prepared following proceduresanalogous to those described in Example 44:

Cpd. No. Name I-7A(3R)-N-(1-amino-3-cyclopentylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-9A(3R)-N-((R)-3-tert-butoxy-1-aminopropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide I-29AN-(1-amino-4-(trifluoromethyl)pentan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide

Example 46(2S)-1-(N-(aminocarbonylmethyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine

Step 1. (S)-tert-Butyl 1-cyclohexyl-3-oxopropan-2-ylcarbamate

To a stirred solution of tert-butyl(S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (0.23 g, 0.9 mmol) in1,2-dichloroethane (5 mL), was added Dess-Martin periodinane (0.49 g,1.34 mmol). The resulting mixture was heated in a CEM microwavesynthesizer at 70° C. for 3 min, diluted with ether (100 mL), and washedwith 1 N NaOH (2×10 mL). The ether layer was dried over Na₂SO₄, and thesolvent was removed in vacuo to give (S)-tert-butyl1-cyclohexyl-3-oxopropan-2-ylcarbamate as an oil. MS ESI +ve m/z 256(M+1).

Step 2. tert-butyl(S)-1-(carbamoylmethylamino)-3-cyclohexyl-propan-2-ylcarbamate

To a solution of 2-aminoacetamide hydrochloride (0.13 g, 1.13 mmol) inMeOH (1 mL) was added KOH (18 mg). When the solid had completelydissolved, the tert-butyl (S)-2-cyclohexyl-1-formylethylcarbamate fromStep 1 was added in one portion, and the resulting suspension wasstirred for 15 minutes. A solution of sodium cyanoborohydride (0.18 g,2.7 mmol) in MeOH (1 mL) was added dropwise. The resulting solution wasstirred at rt until no aldehyde remained (˜40 min). The solvent wasremoved under vacuum and the residue was distributed between ether andwater (10 mL/10 mL). The water layer was extracted with ether (2×5 mL).The combined ether layers were dried, and solvent was removed undervacuum to give tert-butyl(S)-1-(carbamoylmethylamino)-3-cyclohexyl-propan-2-ylcarbamate as anoil, which was used for the next step without purification. MS ESI +vem/z 314 (M+1).

Step 3.N¹-(tert-butoxycarbonyl)-N²-(2-(trimethylsilyl)ethoxycarbonyl)-N²-(aminocarbonylmethyl)-(S)-3-cyclohexylpropane-1,2-diamine

To a solution of tert-butyl(S)-1-(carbamoylmethylamino)-3-cyclohexylpropan-2-ylcarbamate from Step2 in acetone (4 mL) and water (2 mL), was added NaHCO₃ (0.23 g, 2.7mmol) followed by1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (excess). Themixture was stirred at rt for 2 h, acetone was removed in vacuo, and theaqueous layer was extracted with CH₂Cl₂. After removing solvent undervacuum, the residue was purified by flash chromatography on a silica gelcolumn to giveN¹-(tert-butoxycarbonyl)-N²-(2-(trimethylsilyl)ethoxycarbonyl)-N²-(aminocarbonylmethyl)-(S)-3-cyclohexylpropane-1,2-diamine(183.2 mg, 44% in three steps). MS ESI +ve m/z 480 (M+Na).

Step 4.(2S)-1-(N-(aminocarbonylmethyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amine

To a solution of aboveN¹-(tert-butoxycarbonyl)-N²-(2-(trimethylsilyl)ethoxycarbonyl)-N²-(aminocarbonylmethyl)-(S)-3-cyclohexylpropane-1,2-diaminein ether (2 mL) was added TsOH.H₂O (36.9 mg, 0.22 mmol) in ethanol (1mL). The resulting solution was put on a rotatory vaporator, ether wasremoved in vacuum at rt, the bath temperature was raised to 60-65° C.,and the mixture was heated in vacuo for 30 min to give(2S)-1-(N-(aminocarbonylmethyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropyl-2-amineas a p-toluenesulfonic acid salt. MS ESI +ve m/z 358 (M+1).

Example 47(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol

Step 1. (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine

At −20° C., 3-chlorophenyl magnesium chloride (11 mL, 5.5 mmol, 0.5M THFsolution) was added dropwise to a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (500 mg, 1.84mmol) in THF (5 mL). The solution was stirred for 2 h and allowed towarm to rt. The reaction was quenched with satd ammonium chloridesolution. The aqueous layer was extracted with ether (3×). The combinedorganic layers were washed with brine, dried over MgSO₄ and filtered.Evaporation of solvent provided(3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine (0.79 g) asan oil that was used without purification.

Step 2. 4,4-difluoropentylmagnesium chloride

To a solution of 5-chloropentan-2-one (19.0 mL, 166 mmol) in CH₂Cl₂ (50mL) was added Deoxo-Fluor™ (bis-(2-methoxyethyl)aminosulfur trifluoride,41.6 mL, 226 mmol) in CH₂Cl₂ (30 mL) followed by ethanol (1.9 mL, 33mmol). The mixture was stirred at rt overnight. Reaction was pouredslowly into satd NaHCO3 solution. The aqueous layer was extracted withCH₂Cl₂ (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, and filtered. After evaporation of solvent, the crudeproduct was distilled under reduced pressure to afford1-chloro-4,4-difluoropentane as a clear liquid (7 g). ¹H NMR (400 MHz,CDCl₃) δ 3.59 (t, 2H, J=5 Hz), 2.02-1.97 (m, 4H), 1.62 (t, 3H, J=18 Hz).

To Rieke Mg® (1M suspension of finely divided Mg in THF, 7 mL, 7 mmol)at reflux, 1-chloro-4,4-difluoropentane (1.7 mL, 6.9 mmol) was addeddropwise. The mixture was maintained at reflux for 2 h and used in Step3.

Step 3.(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol

A solution of (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine(100 mg, 0.33 mmol) in THF (2 mL) was cooled to −20° C. and4,4-difluoropentylmagnesium chloride (˜0.79M in THF, 5.0 mL, 4.0 mmol)was added. The mixture was stirred for 2 h and quenched with sat'dNH₄Cl. The aqueous layer was extracted with ether. The combined organiclayers were washed with brine, dried over sodium sulfate and filtered.The solvent was removed on a roto-evaporator. The crude product waspurified using flash chromatography (hexanes/EtOAc).N-Boc-(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-olwas isolated as an oil (70 mg) MS m/z 454 (M+Na).

N-Boc-(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol(70 mg, 0.16 mmol) was dissolved in acetonitrile (16 mL) and 2M aq HCl(16 mL) and allowed to stir at rt overnight. The solvent was removedunder high vacuum. The crude material was redissolved in CH₂Cl₂ andwashed with satd NaHCO₃ 2×. The aqueous layer was extracted with CH₂Cl₂3×. The combined organic layers were washed with brine and dried oversodium sulfate. After removing solvent under vacuum(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol wasisolated as an oil (28 mg) MS m/z 332 (M+H⁺).

Example 48(S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. (R)-tert-butyl3-(benzo[b]thiophene-2-carbonyl)piperidine-1-carboxylate

A solution of benzothiophene (117 μL, 1 mmol) in dry THF (4 mL) wascooled to −70° C. A solution of 1.6M n-BuLi in hexanes (950 μL, 1.5equiv) was added dropwise. After 10 min, a solution of Weinreb amide(282 mg, 1 equiv) in dry THF (2.5 mL) was added dropwise. The mixturewas allowed to warm to rt and stirred overnight. Sat'd aq NH₄Cl (30 mL)was added and the mixture was extracted with ether (2×50 mL). Thecombined ether layers were washed with brine (20 mL) and dried overNa₂SO₄. After concentration, the crude product was purified bychromatography on a 12-g silica cartridge eluted with a gradient from 0to 15% EtOAc in hexanes to afford (R)-tert-butyl3-(benzo[b]thiophene-2-carbonyl)piperidine-1-carboxylate (292 mg, 85%).

Step 2. (R)-tert-butyl3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A solution of (R)-tert-butyl3-(benzo[b]thiophene-2-carbonyl)piperidine-1-carboxylate (146 mg, 0.423mmol) in dry THF (5 mL) was cooled to −70° C. A solution of 1.34 M4-methoxybutylmagnesium chloride in THF (630 μL, 2 equiv) was addedslowly. After 10 min, the reaction mixture was allowed to warm up to rtslowly and stirred for another 2 h. Sat'd aq NH₄Cl (20 mL) was added andthe mixture was extracted with ether (2×40 mL). The combined etherlayers were washed with brine (20 mL) and dried over Na₂SO₄. Afterconcentration, the crude product was purified by chromatography on a12-g silica cartridge eluted with a gradient from 0 to 35% EtOAc inhexanes to afford (R)-tert-butyl3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(160.7 mg, 88%).

Step 3.(S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride

(R)-tert-butyl3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(160 mg, 0.37 mmol) was dissolved in 1:1 2 N aq HClsolution/acetonitrile (50 mL). The mixture was stirred overnight at rtand neutralized with 5% aq NaOH. The acetonitrile was removed byevaporation. The aqueous residue was extracted by CH₂Cl₂ (2×40 mL). Thecombined organic layers were concentrated to afford(S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(102 mg, 83%) which was used without purification.

Example 49

The following piperidines were prepared using procedures analogous tothose described in Example 48 using the heterocycle and base indicatedbelow in Step 1.

-   (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2,2-difluorobenzo[d][1,3]dioxole and s-BuLi in Step 1.-   (S)-5-methoxy-1-(1-methyl-1H-imidazol-2-yl)-1-((R)-piperidin-3-yl)pentan-1-ol    using 1-methylimidazole and n-BuLi in Step 1.-   1-(5-chloro-1-methyl-1H-imidazol-2-yl)-5-methoxy-1-(piperidin-3-yl)pentan-1-ol    using 5-chloro-1-methyl-1H-imidazole and n-BuLi in Step 1.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(thiazol-2-yl)pentan-1-ol    using thiazole and n-BuLi in Step 1.-   (S)-5-methoxy-1-(5-methylthiazol-2-yl)-1-((R)-piperidin-3-yl)pentan-1-ol    using 5-methylthiazole and n-BuLi in Step 1.-   4-chloro-2-((R)-(3-methoxypropoxy)((R)-piperidin-3-yl)methyl)pyridine    using 4-chloropyridine and n-BuLi/Me₂N(CH₂)₂OLi in Step 1.

Example 50 Halodiphenyl Ethers from Halophenols and Benzeneboronic Acids1-(3-Fluorophenoxy)-2-bromobenzene

To a stirred solution of 3-fluorophenylboronic acid (2.10 g, 15 mmol),2-bromophenol (1.77 g, 10 mmol) and Cu(OAc)₂ (0.93 g, 5 mmol) inanhydrous CH₂Cl₂ (25 mL) was added activated 4 Å molecular sieves (˜0.1g), followed by anhydrous Et₃N (3.5 mL, 25 mmol). The resulting darkgreen solution was stirred at rt for 48 h. The mixture was evaporatedunder reduced pressure and the residue was washed several times withEt₂O (˜150 mL). The Et₂O solution was washed with sat'd aq NH₄Cl, and 1N aq HCl. The organic layer was evaporated and the crude product waspurified by flash column chromatography to give1-(3-fluorophenoxy)-2-bromobenzene (1.28 g, 48%) as clear oil.

Example 51

The following halodiphenyl ethers were prepared following proceduresanalogous to those described in Example 50.

Halodiphenyl ether Phenol Boronic Acid 1-(2-ethylphenoxy)-2-2-bromophenol 2-ethylphenylboronic acid bromobenzene1-(4-fluorophenoxy)-2- 2-bromophenol 4-fluorophenylboronic acidbromobenzene 1-(2-bromophenoxy)-3- 2-bromophenol 3-methylphenylboronicmethylbenzene acid 2-(o-tolyloxy)-1-bromo-3- 2-bromo-6-methylphenol2-methylphenylboronic methylbenzene acid 2-(o-tolyloxy)-1-bromo-3,5-2-bromo-4,6-difluorophenol 2-methylphenylboronic difluorobenzene acid1-(4-fluoro-2- 2-bromophenol 4-fluoro-2- methylphenoxy)-2-methylphenylboronic acid bromobenzene 1-(5-fluoro-2- 2-bromophenol5-fluoro-2- methylphenoxy)-2- methylphenylboronic acid bromobenzene1-chloro-3-fluoro-2- 2-chloro-6-fluorophenol phenylboronic acidphenoxybenzene 2-(p-tolyloxy)-1-chloro-3- 2-chloro-6-fluorophenol4-methylphenylboronic fluorobenzene acid 2-bromo-4-fluoro-1-(4-2-bromo-6-fluorophenol 2-methylphenylboronic fluorophenoxy)benzene acid2-bromo-4-fluoro-1- 2-bromo-4-fluorophenol phenylboronic acidphenoxybenzene 2-bromo-4-fluoro-1-(4- 2-bromo-4-fluorophenol4-fluorophenylboronic fluorophenoxy)benzene acid

Example 52 1-(o-tolyloxy)-2-iodobenzene

To a solution of 2-(o-tolyloxy)aniline (40 g, 0.2 mol) in 1N aq HCl (400mL, 0.4 mol, 2 equiv) cooled to 0° C. was added dropwise a solution ofNaNO₂ (18 g, 0.26 mol, 1.3 equiv) in water (520 mL). The mixture wasstirred for 1 h at 0° C. and a solution of KI (83 g, 0.5 mol, 2.5 equiv)in water (500 mL) was added dropwise with vigorous stirring. After 0.5 hthe mixture was warmed to 90-100° C. for 1 h, cooled to rt and washedwith sat'd NaHSO₃ until the aqueous layer become clear. The mixture wasextracted with EtOAc (3×200 mL) and the combined organic layers werewashed with aq Na₂S₂O₄ and dried over Na₂SO₄. After evaporation of thesolvent, the solution was passed through a short silica gel column toafford 1-(o-tolyloxy)-2-iodobenzene (40.0 g, 65%).

Example 53 1-(2-Iodophenoxy)-2-chlorobenzene

Step 1. 1-(2-Iodophenoxy)-2-nitrobenzene

To a solution of 2-iodophenol (11.82 g, 52.7 mmol) and1-fluoro-2-nitrobenzene (5.0 g, 35.1 mmol) in DMSO (50 mL was addedK₂CO₃ (14.5 g, 105.3 mmol), followed by CsF (8.0 g, 52.7 mmol). Theresulting suspension was stirred at 50° C. until no starting materialremained (˜5 h), cooled to rt and partitioned between water (50 mL) andCH₂Cl₂ (50 mL). The water layer was separated and extracted with CH₂Cl₂(2×10 mL). The combined organic layers were washed with 1 aq N NaOH (10mL) and brine, and dried over Na₂SO₄. Solvent was removed under vacuumto give 1-(2-iodophenoxy)-2-nitrobenzene (11.2 g, 93%) as an oil, whichwas used for next step without purification.

Step 2. 2-(2-Iodophenoxy)benzenamine

A solution of 1-(2-iodophenoxy)-2-nitrobenzene (9.60 g, 28.1 mmol) andSnCl.2H₂O (13.0 g, 56.0 mmol) in ethanol (25 mL) and water (5 mL) wasrefluxed until no starting material remained (˜1 h). The ethanol wasremoved in vacuo and the aq layer was basified to pH>10 and extractedwith CH₂Cl₂ (4×10 mL). The combined organic layers were dried overNa₂SO₄, and the solvent was removed to give a crude2-(2-Iodophenoxy)benzenamine (8.57 g, 98%), which was used for the nextstep without purification.

Step 3. 1-(2-Iodophenoxy)-2-chlorobenzene

A solution of crude 2-(2-iodophenoxy)benzenamine (8.57 g, 27.6 mmol) inMeCN (60 mL) was cooled to 0° C. and treated with HBF₄ (54 wt % in Et₂O,4.93 mL, 35.9 mmol). The reaction mixture was stirred at 0° C. for 5 minand of t-BuONO (4.10 g, 35.9 mmol) was added dropwise. The resultingmixture was stirred at 0° C. for 10 min, cooled to −20° C., and added toa solution of CuCl (41 g, 414.1 mmol) and CuCl₂ (70 g, 414.1 mmol) inwater (500 mL) at 0° C. The mixture was stirred vigorously at 25° C. for2 h, and partitioned between EtOAc and water. The water layer wasextracted with EtOAc (3×10 mL) and the combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated under vacuum.Flash column chromatography gave 1-(2-iodophenoxy)-2-chlorobenzene (5.35g, 58%).

Example 54

The following halodiphenyl ethers were prepared following proceduresanalogous to those described in Example 52 using the starting materialsand reagents indicated:

Halopdiphenyl ether Phenol in Step 1 Halide in Step 31-(2-iodophenoxy)-2- 2-(trifluoromethyl)phenol KI(trifluoromethyl)benzene 1-(2-iodophenoxy)-2- 2-fluorophenol KIfluorobenzene

Example 55(S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. 2-(phenoxy)phenyllithium

To a solution of diphenyl ether (8.60 g, 50.0 mmol) in Et₂O (75 mL) wasadded n-BuLi (1.6 M in hexane, 32.8 mL, 52.5 mmol). The mixture wasrefluxed for 48 h, and the resulting solution of2-(phenoxy)phenyllithium was used in the next step without any furtheranalysis.

Step 2. (3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine

To a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (4.40 g, 16.2mmol) in anhydrous THF (18 mL) at −10° C., was added dropwise thesolution of 2-phenoxyphenyllithium prepared in Step 1 (80 mL, 32 mmol).The mixture was then warmed to rt, and stirred until no startingmaterial remained (˜30 min). The reaction was quenched with 1 N HCl (˜30mL) and extracted with Et₂O (4×10 mL). The combined organic layers werewashed with sat'd aq NaHCO₃ and brine, and dried over Na₂SO₄. Thesolvent was removed to give(3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (7.44 g,quantitative).

Step 3. (R)-tert-Butyl3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate

To a solution of(3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (6.17 g,16.2 mmol) in THF (30 mL) at −10° C. was added dropwise 2.54 M4-methoxybutylmagnesium chloride in THF (15 mL, 38 mmol). The resultingsolution was warmed to rt slowly, and stirred over night. The reactionwas quenched with sat'd NH₄Cl (10 mL) and extracted with Et₂O (4×10 mL).The combined organic layers were washed with water and brine. Thesolvent was removed and the residue was purified by flash chromatographyto give (R)-tert-butyl3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate(1.97 g, 26% from (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate).

Step 4.(S)-5-Methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol

To a solution of (R)-tert-butyl3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate (1.97 g, 4.19 mmol) in MeCN (100 mL) wasadded 2 N aq HCl (100 mL) slowly at rt. The resulting solution wasstirred at rt until no starting material remained (˜16 h), basified topH=10 with 10 N aq NaOH, and evaporated under reduced pressure to removeMeCN. The aq layer was extracted with CH₂Cl₂ (4×10 mL). The combinedorganic layers were washed with brine and dried over Na₂SO₄. The solventwas removed in vacuo to afford(S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol(1.56 g, quantitative) as a free amine.

Example 56(S)-1-(2-(3-Fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. 2-(3-fluorophenoxy)phenyllithium

To a stirred solution of 1-(3-fluorophenoxy)-2-bromobenzene (1.27 g,4.75 mmol) in THF (10 mL) at −70° C. was added 1.7 M t-BuLi in pentane(5.6 mL, 9.50 mmol) dropwise to keep the temperature below −70° C. Theresulting solution was stirred at −70° C. for 30 min, and used for thenext step directly.

Step 2.(3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine

To a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (0.65 g, 2.37mmol) in THF (4 mL) at −20° C. was added dropwise the solution of2-(3-fluorophenoxy)phenyllithium prepared in Step 2 above. After theaddition was complete, the resulting solution was allowed to warm to rtslowly, and left at rt for 1 h. The reaction was quenched with 1N HCl(˜6 mL), and extracted with Et₂O (4×10 mL). The combined organic layerswere washed with sat'd aq NaHCO₃ and brine, and dried over Na₂SO₄.Removal of the solvent left the crude ketone (1.49 g, quantitative),which was used for next step without further purification.

Step 3. (R)-tert-Butyl3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

To a solution of(3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine(0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise.The resulting solution was warmed to rt slowly, and the completion ofreaction was confirmed by LC-MS (˜20 min). The reaction was quenchedwith sat'd aq NH₄Cl (4 mL) and extracted with Et₂O (4×5 mL). Thecombined organic layers were washed with water and brine, and thesolvent was removed in vacuo to give a crude product which was purifiedby flash column chromatography to afford (R)-tert-butyl3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(0.50 g, 43%).

Step 4.(S)-1-(2-(3-Fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

To a solution of (R)-tert-butyl3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 1.03 mmol) in MeCN (60 mL) wasadded 2 N aq HCl (60 mL) slowly at rt. The resulting solution wasstirred at rt overnight, then basified to pH=10 with 10 N aq NaOH. Themixture was evaporated under reduced pressure to remove MeCN. The aqlayer was extracted with CH₂Cl₂ (4×10 mL), and the combined organiclayers were washed with brine and dried over Na₂SO₄. The solvent wasremoved under vacuum to give(S)-1-(2-(3-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(0.40 g, quantitative) as a free amine.

Example 57

The following piperidines were prepared following procedures analogousto those described in Example 56 using the halodiphenyl ethers listedbelow in Step 1.

Piperidine Halodiphenyl ether(S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-1-(2-ethylphenoxy)-2-bromobenzene ((R)-piperidin-3-yl)pentan-1-ol(S)-1-(2-(4-fluorophenoxy)phenyl)-5-methoxy-1-(4-fluorophenoxy)-2-bromobenzene 1-((R)-piperidin-3-yl)pentan-1-ol(S)-1-(2-(m-tolyloxy)phenyl)-5-methoxy-1-((R)- 1-(2-bromophenoxy)-3-piperidin-3-yl)pentan-1-ol methylbenzene(S)-1-(2-(o-tolyloxy)-3-methylphenyl)-5- 2-(o-tolyloxy)-1-bromo-3-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol methylbenzene(S)-1-(2-(o-tolyloxy)-3,5-difluorophenyl)-5- 2-(o-tolyloxy)-1-bromo-3,5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol difluorobenzene(S)-1-(2-(4-fluoro-2-methylphenoxy)phenyl)-5-1-(4-fluoro-2-methylphenoxy)-2-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol bromobenzene(S)-1-(2-(5-fluoro-2-methylphenoxy)phenyl)-5-1-(5-fluoro-2-methylphenoxy)-2-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol bromobenzene(S)-1-(3,5-difluoro-2-phenoxyphenyl)-5- 2-(o-tolyloxy)-1-bromo-3,5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol difluorobenzene(S)-1-(5-fluoro-2-phenoxyphenyl)-5-methoxy-1-2-bromo-4-fluoro-1-phenoxybenzene ((R)-piperidin-3-yl)pentan-1-ol(S)-1-(3-fluoro-2-(o-tolyloxy)phenyl)-5-methoxy- 1-bromo-3-fluoro-2-(o-1-((R)-piperidin-3-yl)pentan-1-ol tolyloxy)benzene(S)-5-methoxy-1-(3-methyl-2-(o- 1-bromo-3-methyl-2-(o-tolyloxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1- tolyloxy)benzene ol(S)-1-(5-fluoro-2-(4-fluorophenoxy)phenyl)-5- 2-bromo-4-fluoro-1-(4-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol fluorophenoxy)benzene

Example 58

The following piperidines were prepared following procedures analogousto those described in Example 56 except that in Step 1 Grignard reagentswere prepared from the halodiphenyl ethers listed below instead oforganolithiums.

Piperidine Halodiphenyl ether(S)-1-(3-fluoro-2-phenoxyphenyl)-5-methoxy-1- 1-chloro-3-fluoro-2-((R)-piperidin-3-yl)pentan-1-ol phenoxybenzene(S)-1-(2-(p-tolyloxy)-3-fluorophenyl)-5-methoxy- 2-(p-tolyloxy)-1-1-((R)-piperidin-3-yl)pentan-1-ol chloro-3- fluorobenzene

Example 59(S)-1-(2-(o-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1.(2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone

To a solution of 1-(o-tolyloxy)-2-iodobenzene (40 g, 0.13 mol) inanhydrous THF (500 mL) cooled to −78° C. was added dropwise 1.6 M n-BuLiin hexanes (52 mL, 0.13 mol). After stirring for 1 h at −78° C., asolution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (35 g, 0.13mol) in anhydrous THF (500 mL) was added dropwise. The mixture wasallowed to warm to rt and stirred overnight. Sat'd aq NH₄Cl (500 mL) wasadded and the mixture was extracted with EtOAc (3×150 mL). The combinedorganic layers were dried over Na₂SO₄. Solvent removal and flash columnchromatography afforded(2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone(23 g, 45%).

Step 2. (R)-tert-butyl3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A 500-mL, three-necked flask was charged with magnesium turnings (12 g,0.5 mol) and a small crystal of iodine. The flask was evacuated andrefilled with N₂. A solution of 1-chloro-4-methoxybutane (50 g, 0.4 mol)in THF (200 mL) was added dropwise to the mixture. The reaction mixturewas stirred at reflux for 2 h and most of magnesium was consumed. Thesolution of Grignard reagent was cooled to rt.

A 1000-mL, three-necked flask was charged with the(2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone(20 g, 0.05 mol) and THF (250 mL). The flask was evacuated and refilledwith N₂, the mixture was cooled with a dry ice-acetone bath and theGrignard reagent was added dropwise. The mixture was allowed to warmslowly to rt and stirred overnight. After quenching with sat'd aq NH₄Cl(500 mL), the mixture was extracted with EtOAc (3×150 mL) and thecombined organic layers were dried over Na₂SO₄. The solvent was removedand the crude product was purified by flash column chromatography toafford the (R)-tert-butyl3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(20 g, 83%).

Step 3.(S)-1-(2-(o-tolyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

The Boc protecting group was removed using the protocol described inExample 56 Step 4.

Example 60

The following piperidines were prepared using the procedures analogousto those described above from the halodiphenyl ether indicated.

Piperidine Iododiphenyl ether (S)-1-(2-(2-chlorophenoxy)phenyl)-5-1-(2-iodophenoxy)-2- methoxy-1-((R)-piperidin-3-yl)pentan-1-olchlorobenzene (S)-1-(2-(2-(trifluoromethyl)phenoxy)phenyl)-1-(2-iodophenoxy)-2- 5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(trifluoromethyl)benzene (S)-1-(2-(2-fluorophenoxy)phenyl)-5-methoxy-1-(2-iodophenoxy)-2- 1-((R)-piperidin-3-yl)pentan-1-ol fluorobenzene(S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2- 1-(3-pyridyloxy)-2-(pyridin-4-yloxy)phenyl)pentan-1-ol bromobenzene

Example 61(S)-5-methoxy-1-(2-(2,2-(dimethyl)propoxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride

Step 1. Bromo-2-[(tert-butyl)dimethylsiloxy]benzene

A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 118 mmol)and tert-butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) wasstirred at rt overnight. The reaction was treated with water (150 mL)and extracted with Et₂O (4×25 mL). The organic phase was washed with 50%aq lithium chloride solution twice, dried over MgSO₄ and filtered. Thesolvent was evaporated and the crude product was purified by filtrationthrough silica gel, washing with 1:1 EtOAc/hexanes to affordbromo-2-[(tert-butyl)dimethylsiloxy]benzene (13.4 g, 99%).

Step 2.2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene

A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4mmol) in Et₂O (35 mL) was cooled to −78° C. and treated with 1.7 Mtert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirredfor 30 min and a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7mmol) in Et₂O was added slowly. The reaction was allowed to stir andwarm to rt over a two hour period. Sat'd aq ammonium chloride was addedto quench the reaction. The aq phase was extracted with Et₂O threetimes. The combined organic layers were washed with brine and dried overMgSO₄. The solvent was removed by evaporation and the crude product waspurified by flash chromatography on silica gel eluting withEtOAc/hexanes to give a mixture of(2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanoneand (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C.solution of the crude mixture in tetrahydrofuran was treated with 1.3 M4-methoxybutylmagensium chloride in THF (14.9 mL, 19.4 mmol). Thereaction was stirred and allowed to warm to rt over a two hour period.The reaction was quenched with ammonium chloride. The aq layer wasextracted with Et₂O. The combined organic layers were dried over MgSO₄and filtered. The solvent was evaporated and the crude product waspurified by flash chromatography on silica gel eluting withEtOAc/hexanes to afford2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene(874 mg, 47%) and2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol(650 mg, 45%).

To a solution of2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene(710 mg, 1.40 mmol) in tetrahydrofuran (7 mL) was added 1Mtetrabutylammonium fluoride in THF (2.1 mL, 2.1 mmol). The mixture wasstirred at rt for one hour. The mixture was diluted with EtOAc (20 mL)and washed with brine twice. The organic layer was dried over sodiumsulfate and filtered. The filtrate was evaporated to give a residue,which was purified by flash chromatography on silica gel eluting withEtOAc/hexanes to give2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene(450 mg, 81%).

Step 3.((S)-5-methoxy-1-(2-(2,2-(dimethyl)propoxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride

A solution of2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol(195 mg, 0.500 mmol), 1-bromo-2,2-dimethylpropane (1.0 ml, 7.5 mmol),and cesium carbonate (230 mg, 0.71) in NMP (2 mL) was heated and stirredin a microwave reactor for 20 min at 130° C. After removal of solvent,the mixture was redissolved in CH₂Cl₂ and filtered. The filtrate wasevaporated to give a residue which was used without any furtherpurification.

A solution of crude(R)-tert-butyl-3-((S)-1-hydroxy-5-methoxy-1-(2-(2,2-(dimethyl)propoxy)phenyl)pentyl)piperidine-1-carboxylatein MeCN (50 mL) was treated with 2M aq hydrochloric acid (50 mL) andstirred at rt overnight. The solvent was evaporated to afford((S)-5-methoxy-1-(2-(2,2-(dimethyl)propoxy)phenyl)-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride (122 mg, 67%) as an oil.

Example 62

The following piperidines were prepared following procedures analogousto those described in Example 61, replacing 1-bromo-2,2-dimethylpropanein Step 3 with the alkylating agent indicated and using DMF as solventat rt in place of NMP at elevated temperature:

Piperidine Alkyl halide1-(2-(cyclopentylmethoxy)phenyl)-5-methoxy-1-((R)-bromomethylcyclopentane piperidin-3-yl)pentan-1-ol1-(2-(cyclopentyloxy)phenyl)-5-methoxy-1-((R)- bromocyclopentanepiperidin-3-yl)pentan-1-ol1-(2-(cyclobutylmethoxy)phenyl)-5-methoxy-1-((R)- bromomethylcyclobutanepiperidin-3-yl)pentan-1-ol1-(2-(cyclopropylmethoxy)phenyl)-5-methoxy-1-((R)-bromomethylcyclopropane piperidin-3-yl)pentan-1-ol1-(2-(2-cyclopropylethoxy)phenyl)-5-methoxy-1-((R)- (2-piperidin-3-yl)pentan-1-ol bromoethyl)cyclopropane1-(2-(benzyloxy)phenyl)-5-methoxy-1-((R)-piperidin-3- benzyl bromideyl)pentan-1-ol 1-(2-(4-fluorobenzyloxy)phenyl)-5-methoxy-1-((R)-4-fluorobenzyl bromide piperidin-3-yl)pentan-1-ol1-(2-(cyclohexylmethoxy)phenyl)-5-methoxy-1-((R)- bromomethylcyclohexanepiperidin-3-yl)pentan-1-ol

Example 63 (3R)-tert-butyl3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

Step 1.(3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine

To a solution of 2-bromo-2-chloro-biphenyl (5.34 g, 20 mmol) inanhydrous THF (50 mL) cooled to −78° C. was added dropwise a solution of1.6 M n-BuLi in hexane (12.5 mL, 20 mmol). The reaction mixture wasstirred at −78° C. for 1 h and a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (5.44 g, 20mmol) in anhydrous THF (50 mL) was added. The mixture was allowed towarm to rt and stirred overnight. The mixture was quenched with sat'd aqNH₄Cl (100 mL) and extracted with EtOAc (3×75 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated to give the crudeproduct, which was purified by flash column chromatography to afford(3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine(4.43 g, 55%).

Step 2. (3R)-tert-butyl3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate

A 250-mL three-necked flask was charged with magnesium turning (2.88 g,0.12 mol) and a small crystal of iodine. The flask was evacuated andrefilled with N₂. A solution of 1-chloro-4-methoxybutane (15 g, 0.12mol) in THF (60 mL) was added dropwise to the above mixture. Afterheating under reflux for 2 h most of magnesium had been consumed and theGrignard solution was cooled to rt. A 250-mL three-necked flask wascharged with(3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine(4.43 g, 11 mmol) and THF (50 ml), evacuated and refilled with N₂. Themixture was cooled in a dry ice-acetone bath and the Grignard reagentwas added dropwise. The mixture was allowed to warm slowly to rt andstirred overnight. The mixture was quenched with sat'd aq NH₄Cl (100 mL)and extracted with EtOAc. The combined organic layers were dried overNa₂SO₄ and concentrated to give the crude product which was purified byflash column chromatography to afford pure (3R)-tert-butyl3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(2.5 g, 47%).

Example 64

The following piperidines were prepared following procedures analogousto those described in Example 63 employing the bromobiphenyls indicatedin Step 1:

Piperidine Bromobiphenyl(S)-1-(2-phenylphenyl)-5-methoxy-1-((R)-piperidin-3-2-bromo-1,1′-biphenyl yl)pentan-1-ol(S)-1-(2-phenyl-3-fluorophenyl)-5-methoxy-1-((R)-2-bromo-6-fluoro-1,1′-biphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-phenyl-3-chlorophenyl)-5-methoxy-1-((R)-2-bromo-6-chloro-1,1′-biphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-(2-methylphenyl)phenyl)-5-methoxy-1-((R)-2-bromo-2′-methylbiphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-(3-methylphenyl)phenyl)-5-methoxy-1-((R)-2-bromo-3′-methyl-1,1′- piperidin-3-yl)pentan-1-ol biphenyl(S)-1-(2-(4-methylphenyl)phenyl)-5-methoxy-1-((R)-2-bromo-4′-methylbiphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-(2-fluorophenyl)phenyl)-5-methoxy-1-((R)-2-bromo-2′-fluorobiphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-(3-fluorophenyl)phenyl)-5-methoxy-1-((R)-2-bromo-3′-fluorobiphenyl piperidin-3-yl)pentan-1-ol(S)-1-(2-(4-fluorophenyl)phenyl)-5-methoxy-1-((R)-2-bromo-4′-fluorobiphenyl piperidin-3-yl)pentan-1-ol (3R)-tert-butyl3-((S)-1-(2-(4-chlorophenyl)phenyl)-1- 2-bromo-4′-chlorobiphenylhydroxy-5-methoxypentyl)piperidine-1-carboxylate(S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-2-bromo-6-fluoro-3′- ((R)-piperidin-3-yl)pentan-1-ol methylbiphenyl(S)-1-(3′-chloro-6-fluorobiphenyl-2-yl)-5-methoxy-1-2-bromo-3′-chloro-6- ((R)-piperidin-3-yl)pentan-1-ol fluorobiphenyl

Example 65(S)-1-(3-(o-tolyloxy)-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1.(3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)piperidine

A solution of 2.0 mL of 2.0 M n-BuLi (2.0 mL, 4.0 mmol) was addeddropwise to a solution of 1-(o-tolyloxy)-2-fluorobenzene (0.7009 g, 3.5mmol) in THF (15 mL); the internal temperature was maintained below −70°C. during the addition. A pale, yellow slurry resulted. Confirmation ofproton abstraction was confirmed by quenching an aliquot on solid I₂. Asolution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.1159 g, 4.1mmol) in THF (15 mL) was added dropwise. The reaction was permitted towarm to rt and stirred at for 12 h. The reaction was quenched at 0° C.with satd aq NH₄Cl and extracted with Et₂O. The Et₂O extracts werewashed with aq NH₄Cl and brine and dried over Na₂SO₄. Removal of thesolvent left crude(3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)piperidine(1.79 g, ˜80% pure, quantitative) which was used directly withoutfurther purification.

Step 2. (R)-tert-butyl3-((S)-1-(3-(o-tolyloxy)-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate

A solution of crude(3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)-piperidine(1.79 g, ˜80% pure, 3.5 mmol) in THF (15 mL) was cooled to 0° C. A 1.63M solution of 4-methoxybutylmagnesium chloride in THF was added withfast dropwise addition. The reaction was stirred for 1 h at rt, cooledto 0° C. and then quenched with sat'd aq NH₄Cl. The crude mixture wastaken up into Et₂O, washed with sat'd aq NH₄Cl and brine, and dried overNa₂SO₄. Removal of the solvent gave an oil (1.82 g). Flashchromatography on a 40-g silica cartridge eluting with a gradient from 0to 100% EtOAc in hexanes. Appropriate fractions were combined andstripped to give (R)-tert-butyl3-((S)-1-(3-(o-tolyloxy)-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(0.66 g, 30%).

Example 66N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide

Step 1.[3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)propyl]magnesiumbromide

A 250 mL, round bottom flask was charged with magnesium turnings (0.528g, 21.7 mmol, 1.16 equiv) and THF (10 mL). The flask was degassed andheated to 100° C. A small crystal of iodine was then added. A solutionof 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane(5.239 g, 18.7 mmol, 1.0 equiv) in THF (15 mL) was added dropwise to theboiling THF mixture over 10 min. The reaction mixture was stirred andheated under reflux for 2.5 h and most of magnesium was consumed. Theresulting Grignard reagent was used in the next step.

Step 2. (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate

To a 250 mL, round bottom flask were added(3-chlorophenyl)((R)—N-Boc-piperidin-3-yl)methanone (0.800 g, 2.47 mmol)and THF (10 mL). The flask was evacuated and refilled with N₂. Themixture was cooled with a dry ice-acetone bath and the[3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)propyl]magnesiumbromide solution, obtained in Step 1, was added via a cannula. Thereaction mixture was allowed to slowly warm to −8° C. while stirringovernight. The mixture was quenched with 10% aq Na₂CO₃ (10 mL), stirredat rt for 3 h, extracted with CH₂Cl₂ (3×) and dried over Na₂SO₄. Thecrude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μC18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 13 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 3.5 min, flow rate25 mL/min) to give 0.883 g (72%) of TFA salt of (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate.LC-MS (3 min) t_(R)=1.30 min, m/z 383, 385 (MH⁺), 327, 329; ¹H NMR (400MHz, CD₃OD) δ 7.36 (m, 1H), 7.27-7.13 (m, 3H), 4.26 (br s, 1H), 3.89 (d,J=12.9 Hz, 1H), 2.82-2.68 (m, 2H), 2.44 (br s, 1H), 2.36 (t, J=12.2 Hz,1H), 1.97-1.79 (m, 2H), 1.64-1.08 (m, 16H), 1.34 (s); ¹³C NMR (100 MHz,CD₃OD) δ 156.69, 148.15, 135.39, 130.69, 127.74, 127.36, 125.41, 81.04,78.10, 40.95, 28.69, 26.64, 26.51, 23.30.

Step 3. (R)-tert-butyl3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate

To a 100 mL, round bottom flask were added TFA salt of (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate(0.374 g, 0.75 mmol, 1.0 equiv), DMAP (0.1615 g), CH₂Cl₂ (10 mL), andtriethylamine (3 mL). The mixture was cooled in an ice bath and asolution of acetic anhydride (0.280 g, 2.74 mmol, 3.6 equiv) in CH₂Cl₂(10 mL) was added. The reaction mixture was allowed to slowly warm to rtwhile stirring overnight (16 h). After the solvents were removed invacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 1.5 min, flow rate25 mL/min) to give 0.2589 g (81%) of (R)-tert-butyl3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate.LC-MS (3 min) t_(R)=1.72 min, m/z 447, 449 (MNa⁺), 425 (MH⁺), 325, 327;¹H NMR (400 MHz, CDCl₃) δ 7.38-7.37 (m, 1H), 7.28-7.18 (m, 3H), 6.06 (brs, 1H), 4.36-4.34 (m, 1H), 3.97-3.95 (m, 1H), 3.35-3.26 (m, 1H),3.13-3.05 (m, 1H), 2.99 (br s, 2H), 2.55-2.49 (m, 2H), 1.97 (s, 3H),1.44 (s, 9H), 1.95-1.15 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 171.41,155.17, 146.75, 134.24, 129.33, 126.63, 126.01, 123.83, 79.68, 77.60,46.34, 44.69, 39.71, 35.91, 28.43, 25.40, 25.23, 24.15, 22.99.

Step 4.N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide

A mixture of (R)-tert-butyl3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate(0.1773 g, 0.4172 mmol) in CH₃CN (50 mL) and 2 N aq HCl (45 mL) wasvigorously stirred at rt for 24 h. The solvents were removed in vacuo togive the HCl salt ofN—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide,which was used in the next step without further purification. LC-MS (3min) t_(R)=0.91 min, m/z 325, 327 (MH⁺).

Example 67

The following piperidines were prepared following procedures analogousto those described in Example 66:

-   N—((S)-4-(2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (2-fluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone in Step 2.-   N—((S)-4-(2-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (2-fluoro-5-methylphenyl)((R)—N-Boc-piperidin-3-yl)methanone    in Step 2.-   N—((S)-4-(3-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (3-fluoro-5-methylphenyl)((R)—N-Boc-piperidin-3-yl)methanone    in Step 2.-   N—((S)-4-(2,3-difluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (2,3-difluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone in    Step 2.-   N—((S)-4-(3,5-difluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (3,5-difluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone in    Step 2.-   N—((S)-4-(2-chloro-3-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (2-chloro-3-fluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone    in Step 2.-   N—((S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (3-chloro-2-fluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone    in Step 2.-   N—((S)-4-(3-chloro-5-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide    using (3-chloro-5-fluorophenyl)((R)—N-Boc-piperidin-3-yl)methanone    in Step 2.-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2,2,2-trifluoroacetamide    using trifluoroacetic anhydride in Step 3.-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)butyramide    using butyric anhydride in Step 3.-   (R)    —N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2-methoxypropanamide    using (R)-2-methoxypropanoic acid and EDC in place of acetic    anhydride in Step 3.-   (S)—N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-2-methoxypropanamide    using (S)-2-methoxypropanoic acid and EDC in place of acetic    anhydride in Step 3.-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)propionamide    using propionic anhydride in Step 3.-   N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)cyclopropanecarboxamide    using cyclopropanecarboxylic acid and EDC in place of the anhydride    in Step 3.

Example 68(S)-1-(benzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. 1-(2,2-diethoxyethoxy)-2-bromobenzene

A solution of KOH pellets (85%, 0.68 g, 10.3 mmol) in water (1.5 mL) wasadded to 2-bromophenol (1 mL, 8.6 mmol). The mixture was diluted withDMSO (20 mL) and bromoacetaldehyde diethyl acetal (1.43 mL, 9.5 mmol)was added. The mixture was heated at 100° C. for 6 h, cooled to rt,diluted with ether (175 mL), washed with water (3×40 mL) and 5% aq NaOH(40 mL), and dried over MgSO₄. Removal of the solvent left1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, quant) as an oil.

Step 2. 7-bromobenzofuran

A stirred mixture of polyphosphoric acid (˜5 g) and chlorobenzene (8 mL)was heated at reflux and a solution of1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, 9.0 mmol) inchlorobenzene (3 mL) was added dropwise over 10 min. The mixture washeated at reflux for 1.5 h. The mixture was allowed to cool to rt and 1Maq NaOH (20 mL) was added, followed by ether (175 mL). The mixture waswashed with water (2×20 mL) and brine (20 mL), and dried over MgSO₄.Evaporation of the solvent left a residue which was purified by achromatography on a 140-g silica cartridge eluted with hexanes and a0-10% EtOAc in hexanes gradient. Appropriate fractions were pooled andconcentrated to afford 7-bromobenzofuran (0.65 g, 38% from2-bromophenol) as a clear colorless oil.

Step 3. 7-Bromo-2-(trimethylsilyl)benzofuran

A stirred solution of diisopropylamine (0.65 mL, 4.7 mmol) in THF (15 L)was cooled to 5° C. and n-BuLi (2.5 M in hexanes, 1.9 mL, 4.7 mmol) wasadded dropwise over 5 min. The mixture was stirred at 5° C. for 15 minand cooled to −70° C. Chlorotrimethylsilane (0.59 mL, 4.7 mmol) wasadded followed by a solution of 7-bromobenzofuran (0.46 g, 2.35 mmol) inTHF (5 mL). The mixture was stirred at −70° C. for 1.5 h and poured intosat'd aq NH₄Cl (80 mL). The mixture was diluted with 5% aq HCl (20 mL)and extracted with ether (2×80 mL). The combined ether extracts werewashed with sat'd aq NaHCO₃ (50 mL), dried over MgSO₄ and concentratedto leave crude 7-bromo-2-(trimethylsilyl)benzofuran (0.62 g, 98%) as ayellow oil.

Step 4. (R)-tert-butyl3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A stirred solution of 7-bromo-2-(trimethylsilyl)benzofuran (620 mg, 2.3mmol) in THF (15 mL) was cooled to −70° C. and n-BuLi (2.5 M in hexanes,0.85 mL, 2.1 mmol) was added dropwise over 2 min. The mixture wasstirred at −70° C. for 15 min and a solution of (R)-tert-butyl3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (341 mg, 1.30mmol) in THF (5 mL) was added dropwise over 2 min. The mixture wasstirred at −70° C. for 1 h, poured into satd aq NaHCO₃ (100 mL) andextracted with ether (2×100 mL). The combined ether extracts were washedwith brine (40 mL) and dried over MgSO₄. Removal of the solvent affordedcrude (R)-tert-butyl3-((benzofuran-7-yl)carbonyl)piperidine-1-carboxylate (727 mg) as anoil. This material was dissolved in THF (15 mL) and cooled to −70° C.4-Methoxybutylmagnesium chloride (1.52 M in THF, 2.0 mL, 3.04 mmol) wasadded dropwise over 2 min. The mixture was stirred at −70° C. for 2 hand poured into sat'd aq NaHCO₃ (100 mL). The mixture was extracted withether (2×100 mL) and the combined ether extracts were washed with brine(35 mL) and dried over MgSO₄. Removal of the solvent left an oil whichwas purified by chromatography on a 40-g silica cartridge eluted with agradient from 0 to 100% EtOAc in hexanes to afford (R)-tert-butyl3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(240 mg, 44%) as an oil.

Step 4.(S)-1-(benzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

(R)-tert-butyl3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(240 mg, 0.58 mmol) was dissolved in MeCN (20 mL) and 5% aq HCl (10 mL)was added. The mixture was stirred at rt for 1 d and solid K₂CO₃ wasadded. The mixture was diluted with water (40 mL) and extracted withEtOAc (2×100 mL). The combined organic extracts were washed with brine(25 mL), dried over MgSO₄ and concentrated to leave an oil (150 mg)which was purified by reverse phase preparative HPLC to afford(S)-1-(benzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (120mg, 81%) as an oil.

Example 69

The following piperidines were prepared following procedures analogousto those described in Example 68:

-   (S)-5-methoxy-1-(2-methylbenzofuran-7-yl)-1-(R)-piperidin-3-yl)pentan-1-ol    using 7-bromo-2-methylbenzofuran and n-BuLi in Step 4.-   (S)-1-(2-isobutylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 7-bromo-2-isobutylbenzofuran and n-BuLi in Step 4.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(thiophen-3-yl)pentan-1-ol    using 3-bromothiophene and n-BuLi in Step 4.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(pyridin-2-yl)pentan-1-ol    from 2-bromopyridine and n-BuLi in Step 4.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(quinolin-8-yl)pentan-1-ol    from 8-bromoquinoline and n-BuLi in Step 4.-   (S)-1-(1H-indazol-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    from 7-bromoindazole and n-BuLi-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trimethylsilyl)benzo[b]thiophen-7-yl)pentan-1-ol    from 7-bromo-2-(trimethylsilyl)benzothiophene and n-BuLi in Step 4.-   (S)-5-methoxy-1-(2-methylbenzofuran-7-yl)-1-((R)-piperidin-3-yl)pentan-1-ol    from 7-bromo-2-methylbenzofuran and n-BuLi in Step 4.-   (S)-1-(2-fluorobenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    from 7-bromo-2-fluorobenzofuran and n-BuLi in Step 4.-   (S)-1-(5-fluorobenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    from 7-bromo-5-fluoro-2-(trimethylsilyl)benzofuran and n-BuLi in    Step 4.-   (S)-1-(2-tert-butylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    from 7-bromo-2-(t-butyl)benzofuran and n-BuLi in Step 4.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trimethylsilyl)benzo[b]thiophen-4-yl)pentan-1-ol    from 4-bromo-2-(trimethylsilyl)benzothiophene and n-BuLi in Step 4.

Example 70(±)-(RS)-1-(3-chlorophenyl)-5-methoxy-1-((RS)-morpholin-2-yl)pentan-1-ol

Step 1. (±)-tert-butyl2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate

To a stirred solution of(±)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.51 g, 6.53mmol), N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.49 mmol) andi-Pr₂NEt (3.1 mL, 17.6 mmol) in CH₂Cl₂ (30 mL) was added solid HATU(3.01 g, 7.85 mmol). The mixture was stirred at rt for 3 d, diluted withether (175 mL), washed with 5% aq HCl (2×50 mL) and satd aq NaHCO3 (50mL) and dried over MgSO₄. Removal of the solvent left (±)-tert-butyl2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 96%) as anoil.

Step 2. (±)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate

A stirred solution of (±)-tert-butyl2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 6.4 mmol)in dry THF (40 mL) was cooled in an ice-salt bath and 1.34 M4-methoxybutylmagnesium chloride in THF (10 mL, 1.34 mmol) was addeddropwise over 3 min. The cooling bath was allowed to expire and themixture was stirred at rt for 6 h, poured into ice cold 3% aq HCl (100mL) and extracted with ether (2×100 mL). The combined ether extractswere washed with satd aq NaHCO₃ (35 mL), dried over MgSO₄ andconcentrated to afford (±)-tert-butyl2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.78 g, 93%) as an oil.

Step 3. (±)-(R)-tert-butyl2-((R)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate

A stirred solution of (±)-tert-butyl2-(5-methoxypentanoyl)morpholine-4-carboxylate (258 mg, 0.86 mmol) inCH₂Cl₂ (5 mL) was cooled to −70 C and 0.5 M 3-chlorophenylmagnesiumbromide in THF (4 mL, 2.0 mmol) was added dropwise over 5 min. Thecooling bath was allowed to expire. After 1.5 h the mixture had reachedrt and was poured into satd aq NaHCO₃ (50 mL). The mixture was extractedwith ether (2×50 mL). The combined ether extracts were washed with brine(10 mL), dried over MgSO₄ and concentrated to afford an oil (398 mg).This material was chromatographed on a 12-g silica cartridge eluted witha gradient of 0-100% EtOAc in hexanes to afford (±)-(R)-tert-butyl2-((R)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate(274 mg, 76%).

Step 4.(±)-(R)-1-(3-chlorophenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol

(±)-(R)-tert-butyl2-((R)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate(274 mg, 0.66 mmol) was dissolved in MeCN (10 mL) and 5% aq HCl (5 mL)was added. The mixture was stirred at rt for 2 d. Solid K₂CO₃ (˜1 g) wasadded to the mixture, followed by water (25 mL). The mixture wasextracted with ether (2×50 mL). The combined ether extracts were washedwith brine (10 mL), dried over MgSO₄ and concentrated to afford a whitesolid (0.15 g). This material was purified by prep HPLC to afford theTFA salt of(±)-(R)-1-(3-chlorophenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol(163 mg, 55%) as a syrup.

Example 71

The following morpholines were prepared following procedures analogousto those described in Example 70:

-   (RS)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((RS)-morpholin-2-yl)pentan-1-ol-ol    using 2-fluoro-3-chlorophenyllithium and THF as solvent in Step 3.-   (RS)-1-(benzo[b]thiophen-7-yl)-5-methoxy-1-((RS)-morpholin-2-yl)pentan-1-ol    using 7-lithiobenzothiophene, generated from 7-bromobenzothiophene    and n-BuLi, and ether as solvent in Step 3.-   (R)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-morpholin-2-yl)pentan-1-ol    using (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid in    Step 1 and 2-fluoro-3-chlorophenyllithium and THF as solvent in Step    3.

Example 72 1,1,1-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol

Step 1. 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate

Ethyl nipecotate (1.55 mL, 10 mmol), (Boc)₂O (2.4 g, 1.1 equiv),triethylamine (2.8 mL, 2.1 equiv) and dichloromethane (70 mL) were mixedand stirred overnight at rt. The reaction mixture was diluted with EtOAc(200 mL), washed with 5% aq HCl (2×25 mL), sat'd aq NaHCO₃ (30 mL) andbrine (20 mL), and dried over Na₂SO₄. After concentration, the crudeproduct was purified by chromatography on a 40-g silica cartridge elutedwith a 0-30% EtOAc in hexanes gradient to afford 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (2.61 g, 100%) as a clear oil.

Step 2. tert-butyl 3-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate

1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (424 mg, 1.65 mmol)and CsF (ca 10 mg) were combined in a vial under N₂. Dry THF (3 mL) wasadded, followed by Me₃SiCF₃ (256 μL; 1.05 equiv). After stirring for 3h, 4N aq HCl (4 mL) was added to the vial and the mixture was stirredfor 1 h. The mixture was extracted with diethyl ether (2×15 mL). Thecombined organic layers were washed with brine (8 mL), dried overNa₂SO₄, and concentrated to afford tert-butyl3-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (173 mg. 37%)

Step 3. tert-butyl3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate

Under protection of N₂ gas, tert-butyl3-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (102 mg, 0.363 mmol)was dissolved dry THF (8 mL) and cooled to −78° C. (dry ice/acetonebath). 1.22 M methoxybutylmagnesium chloride in THF (600 μL, 2 equiv)solution was added slowly. After 10 min, the reaction was allowed towarm up to rt slowly. After 2 h, satd aq NH₄Cl (15 mL) solution wasadded to the reaction mixture. The mixture was diluted with diethylether and the layers were separated. The aqueous layer was extractedwith diethyl ether (3×10 mL). The combined organic layers were washedwith brine (10 mL) and dried over Na₂SO₄. After concentration, the crudeproduct was purified by prep HPLC to afford tert-butyl3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate(20 mg, 15%).

Step 4. 1,1,1-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol

Tert-butyl3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate(20 mg) was dissolved in 1:1 TFA/dichloromethane (4 mL). The mixture wasstirred for 30 min. The mixture was concentrated to afford1,1,1-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol which was usedwithout purification.

Example 73(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. (R)-tert-butyl3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

To a stirred solution of R-piperidine-1,3-dicarboxylic acid 1-tert-butylester (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230g, 1.42 mol). The mixture was stirred for 1 h in an ice-water bath. Asuspension of triethylamine (207 mL, 1.41 mol) andN,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900mL) was added. The reaction mixture was allowed to warm to rt andstirred overnight. After TLC showed the reaction was complete, solventwas evaporated to give a residue, which was dissolved in CH₂Cl₂ (1.2 L)and washed successively with 0.5 N aq HCl, sat'd aq Na₂CO₃ and brine,dried over anhydrous sodium sulfate and evaporated to give the crudecompound (R)-tert-butyl3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (250 g, 91%),which was used in the next step directly without purification. ¹H NMR(400 MHz, CDCl₃): 1.44 (s, 9H), 1.60-1.78 (m, 2H), 1.90 (m, 1H), 2.65(m, 1H), 2.75-2.85 (m, 2H), 3.16 (s, 3H), 3.71 (s, 3H), 4.05-4.19 (m,2H). MS (E/Z): 273 (M+H⁺).

Step 2. (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate

To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrousTHF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 Mn-BuLi in hexane (31.3 mL, 78.34 mmol). The reaction mixture was stirredat −78° C. for 1 h and a solution of (R)-tert-butyl3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol)in anhydrous THF (50 mL) was added dropwise. After addition, the mixturewas allowed to warm to rt and stirred for 2 h. The mixture was quenchedwith saturated NH₄Cl (250 mL) and extracted with EtOAc (3×150 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (PE/EtOAc 5:95) to give (R)-tert-butyl3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). ¹H NMR (400MHz, CDCl₃): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m,1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H),7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS (E/Z):324 (M+H⁺).

Step 3. (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A 250 mL three-necked flask was charged with magnesium turnings (2.88 g,0.12 mol) and a small crystal of iodine in THF (20 mL). The flask wasevacuated and refilled with N₂. A solution of 1-chloro-4-methoxybutane(15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture.After heating under reflux for 1 h, most of magnesium was consumed, thereaction mixture cooled to rt. Another 250 mL three-necked flask wascharged with (R)-3-(3-chloro-benzoyl)-piperidine-1-carboxylic acidtert-butyl ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuatedand refilled with N₂. The mixture was cooled with dry ice-acetone bathand the Grignard reagent derived from 1-chloro-4-methoxybutane (20 mL)was added dropwise. After addition, the mixture was allowed to warmslowly to rt and stirred for 2 h. The mixture was quenched with sat'd aqNH₄Cl (100 mL), extracted with EtOAc (3×80 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography (EA/PE10:90) to give (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(3.0 g, 73%). ¹H NMR (400 MHz, CDCl₃): 1.45 (s, 9H), 1.52-1.58 (m, 3H),1.75 (m, 1H), 1.92 (m, 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H),3.95 (m, 1H), 4.35 (m, 1H), 7.20-7.26 (m, 3H), 7.36 (m, 1H). MS (E/Z):412 (M+H⁺).

Step 4.(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

(R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(4.1 g, 0.01 mol) was dissolved in 20% TFA/CH₂Cl₂ (40 mL). The reactionmixture was stirred at rt for 2 h, TLC showed the reaction wascompleted. A solution of sat'd aq Na₂CO₃ was added dropwise to adjustthe pH to 8˜9 and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give crude(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (3.0g, 97%), which was used without purification.

Example 74

The compounds listed below were prepared following procedures analogousto those described in Example 73:

-   (S)-1-(3-fluoro-4-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-fluoro-4-methylbromobenzene in Step 2-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2,3,5-trifluorophenyl)pentan-1-ol    using 2,3,5-trifluorobromobenzene in Step 2.-   (S)-5-ethoxy-1-((R)-piperidin-3-yl)-1-(2,3,5-trifluorophenyl)pentan-1-ol    using 2,3,5-trifluorobromobenzene in Step 2 and    4-ethoxybutylmagnesium chloride in Step 3.-   (S)-1-(3-fluoro-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-fluoro-5-methylbromobenzene in Step 2-   (S)-1-(2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-fluorobromobenzene in Step 2.-   (S)-1-(3,5-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3,5-difluorobromobenzene in Step 2.-   (S)-1-(2,3-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2,3-difluorobromobenzene in Step 2.-   (S)-1-(2-fluoro-3-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-fluoro-3-methyliododbenzene in Step 2.-   (S)-1-(3-fluoro-2-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-methyl-3-fluorobromobenzene in Step 2.-   (S)-1-(2-fluoro-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-fluoro-5-methylbromobenzene and n-BuLi in Step 2.-   (S)-1-(5-fluoro-2-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-methyl-5-fluorobromobenzene in Step 2.-   (S)-1-(2-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-chlorobromobenzene in Step 2.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trifluoromethoxy)phenyl)pentan-1-ol    using 2-(trifluoromethoxy)bromobenzene and n-BuLi in Step 2.-   (S)-1-(3,5-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3,5-dimethylbromobenzene in Step 2.-   (S)-5-methoxy-1-(3-(methylthio)phenyl)-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-(methylthio)bromobenzene and n-BuLi in Step 2.-   (S)-1-(2-fluoro-6-methoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-fluoro-6-methoxybromobenzene and n-BuLi in Step 2.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2-(trifluoromethyl)phenyl)pentan-1-ol    using 2-(trifluoromethyl)bromobenzene and n-BuLi in Step 2.-   (S)-1-(5-fluoro-2-methoxyphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-methoxy-5-fluorobromobenzene and n-BuLi in Step 2.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(3-(trifluoromethoxy)phenyl)pentan-1-ol    using 3-(trifluoromethoxy)bromobenzene and n-BuLi in Step 2.-   (S)-1-(3-fluoro-5-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-fluoro-5-methylbromobenzene and n-BuLi in Step 2.-   (S)-1-(2,3-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2,3-dimethylbromobenzene and n-BuLi in Step 2.-   (S)-1-(2,5-dimethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2,5-dimethylbromobenzene and n-BuLi in Step 2.-   (S)-5-methoxy-1-(3-methoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-methoxybromobenzene and n-BuLi in Step 2.-   (S)-1-(2,3-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2,3-difluorobromobenzene and n-BuLi in Step 2.-   (S)-1-(3-chloro-2-methylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-chloro-2-methylbromobenzene and n-BuLi in Step 2.-   (S)-1-(3-chloro-5-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-bromo-5-chloroiodobenzene and n-BuLi in Step 2.-   (S)-1-(3-chloro-2,4-difluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-chloro-2,4-difluorobromobenzene in Step 2.-   (S)-1-(2-(allyloxy)-3-bromophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-allyloxy-1,3-dibromobenzene and n-BuLi in Step 2.-   1-(2-(allyloxy)-5-fluorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-allyloxy-5-fluorobromobenzene and n-BuLi in Step 2.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2,3,5-trifluorophenyl)pentan-1-ol    using 2,3,5-trifluorobromobenzene and n-BuLi in Step 2.

Example 75(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. (R)-tert-butyl3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate

To a stirred solution of 1-chloro-2-fluoro-benzene (13.0 g, 0.1 mol) inTHF (250 mL) at −75° C. was added dropwise 2.5 M BuLi in hexane (40 mL,0.1 mol) during 45 min. After additional stirring for 30 min at −75° C.,a solution of (R)-tert-butyl3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (21.76 g, 0.08mol) in THF (100 mL) was added dropwise over 30 min. The mixture wasallowed to warm from −70° C. to 0° C. The mixture was quenched withsat'd aq NH₄Cl, extracted with EtOAc (3×) and the combined organiclayers were dried over Na₂SO₄. Solvent removal and flash columnchromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (19.2 g, 70%). ¹HNMR (400 MHz, CDCl₃): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1H), 2.06 (m,1H), 2.87 (m, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 3.9 (m, 1H), 4.2 (m, 1H),7.18 (m, 1H), 7.60 (m, 2H). MS (E/Z): 342 (M+H⁺).

Step 2. (R)-tert-butyl3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A flame dried 250 mL three-necked flask was charged with magnesiumturnings (7.02 g, 0.293 mol), a small crystal of iodine and THF (30 mL).The flask was evacuated and refilled with N₂. A solution of1-chloro-4-methoxybutane (28.69 g, 0.234 mol) in THF (120 mL) was addeddropwise slowly to the mixture. The reaction mixture was stirred underreflux for 2.5 h and most of magnesium was consumed. The resultingGrignard reagent was used as follows To another 100 mL three-neckedflask was added (R)-tert-butyl3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (10 g, 0.0293 mol)and THF (100 mL). The flask was evacuated and refilled with N₂. Themixture was cooled with dry ice-acetone bath and the Grignard reagent(250 mL) was added. The reaction mixture was allowed to warm slowly tort while stirring overnight. The mixture was quenched with satd aq NH₄Cl(50 mL), extracted with EtOAc (3×), and the combined organic layers weredried over Na₂SO₄. Evaporation of the solvent gave the crude product.The LC-MS analysis of the crude product indicated the presence of twoisomers (95:5). Flash column chromatography, eluting with 10% EtOAc/PEafforded (R)-tert-butyl3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(9.4 g, 75% yield). ¹H NMR (400 MHz, DMSO): 0.68 (m, 1H), 1.50-1.01 (m,7H), 1.37 (s, 9H), 1.75 (m, 2H), 2.01 (m, 1H), 3.11 (s, 3H), 3.17 (m,2H), 3.85 (m, 1H), 7.2 (t, 1H), 7.45 (m, 2H). MS (E/Z): 430 (M+H⁺).

Step 3.(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

A solution of (R)-tert-butyl3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(100 mg) in 20% TFA/CH₂Cl₂ was stirred at 0° C. for 30 min. The mixturewas neutralized by addition of sat'd aq NaHCO₃, extracted with CH₂Cl₂(3×) and dried over Na₂SO₄. Evaporation of the solvent gave(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(70 mg, 91%), which was used without further purification. ¹H NMR (400MHz, CDCl₃): 0.90 (m, 1H), 1.52-1.24 (m, 6H), 1.78 (m, 1H), 1.83 (m,1H), 1.93 (m, 1H), 2.21 (m, 1H), 2.40 (m, 1H), 2.83 (m, 1H), 3.00 (m,1H), 3.12 (s, 3H), 3.31 (m, 2H), 3.63 (m, 1H), 7.06 (m, 1H), 7.30 (m,1H), 7.55 (t, 1H). MS (E/Z): 330 (M+H⁺).

Example 76

The compounds listed below were prepared following procedures analogousto those described in Example 75:

-   (S)-1-(2,3-dichlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 1,2-dichlorobenzene in Step 1.-   (S)-5-methoxy-1-((R)-piperidin-3-yl)-1-(2,3,4-trifluorophenyl)pentan-1-ol    using 1,2,3-trifluorobenzene in Step 1.-   1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 4-(ethoxy)butylmagnesium chloride in Step 2.-   (S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 1,2-dichlorobenzene in Step 1 and 4-(ethoxy)butylmagnesium    chloride in Step 2.

Example 77(S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

Step 1. (R)-tert-butyl3-(2-(cyclopropylmethoxy)-3-fluorophenyl)piperidin-1-carboxylate

A 50 mL three-necked flask was charged with magnesium turning (240 mg,10 mmol) and a small crystal of iodine. The flash was evacuated andrefilled with N₂. A portion of a solution of1-bromo-2-cyclopropylmethyl-3-fluoro-benzene (2.1 g, 8.57 mmol) in dryTHF (10 mL) was added dropwise to trigger the reaction. When the colorof iodine had disappeared, the residual solution was added dropwiseslowly. The mixture was stirred under reflux for 2.5 h and most ofmagnesium was consumed. The resulting Grignard reagent was used for thenext step. To another 100-mL three-necked flask was added (R)-tert-butyl3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (1.55 g, 5.7 mmol)and THF (15 mL). The flask was evacuated and refilled with N₂. Themixture was cooled in a dry ice-acetone bath and the Grignard reagentprepared above (10 mL) was added slowly. The reaction mixture wasstirred at −20 to −10° C. for 2.5 h. The mixture was quenched with sat'daq NH₄Cl (20 mL), extracted with EtOAc (3×), and the combined organiclayers were dried over Na₂SO₄. Solvent removal and flash columnchromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (1.5g, 70%). ¹H NMR (400 MHz, CDCl₃): 0.27 (m, 2H), 0.57 (m, 2H) 1.20 (m,1H), 1.43 (s, 9H), 1.60-1.51 (m, 4H), 1.73 (m, 1H), 2.02 (m, 1H), 2.79(m, 1H), 3.47 (m, 1H), 3.98 (m, 3H), 4.20 (m, 1H), 7.04 (m, 1H), 7.20(m, 2H). MS (E/Z): 378 (M+H⁺).

Step 2. (R)-tert-butyl3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

A flame dried 50 mL three-necked flask was charged with magnesiumturnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5mL). The flask was evacuated and refilled with N₂. Then a solution of1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was addeddropwise slowly to the mixture. The reaction mixture was stirred underreflux for 2.5 h and most of the magnesium was consumed. The resultingGrignard reagent was used as follows. To another 100 mL three-neckedflask was added (R)-tert-butyl3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled withN₂. The mixture was cooled with a dry ice-acetone bath and the Grignardreagent (250 mL) was added. The reaction mixture was allowed to warmslowly to rt while stirring overnight. The mixture was quenched withsat'd aq NH₄Cl (10 mL), extracted with EtOAc (3×), and the combinedorganic layers were dried over Na₂SO₄. Evaporation of the solvent andpurification by flash column chromatography, eluting with 10% EtOAc/PEafforded (R)-tert-butyl3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(560 mg, 91%). ¹H NMR (400 MHz, CDCl₃): 0.35 (m, 2H), 0.63 (m, 2H), 1.05(m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H),2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H),4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H⁺).

Step 3.(S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol

A solution of (R)-tert-butyl3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(120 mg) in 20% TFA/CH₂Cl₂ (20 mL) was stirred at 0° C. for 5 min. Thesolvent was neutralized by addition of sat'd aq NaHCO₃, and the mixturewas extracted with CH₂Cl₂ (3×). The combined organic layers were driedover Na₂SO₄ and evaporated to give the crude product. LC-MS analysis ofthe crude product indicated the presence of two isomers (10:1). Thecrude product was purified by reverse phase prep HPLC to afford themajor isomer,(S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(40 mg, 42%). ¹H NMR (400 MHz, CD₄O): 0.36 (m, 2H), 0.63 (m, 2H), 0.86(m, 1H), 1.55-1.11 (m, 11H), 1.82 (m, 1H), 2.29 (m, 2H), 2.45 (m, 1H),2.66 (t, 1H), 2.94 (d, 1H), 3.24 (s, 3H), 3.31 (m, 2H), 3.91 (m, 2H),6.98 (m, 2H), 726 (m, 1H). MS (E/Z): 366 (M+1). In addition,2-fluoro-6-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)phenolwas isolated as a byproduct.

Example 78

The following compounds were prepared using procedures analogous tothose described in Example 77:

-   (S)-1-(2-chloro-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-chloro-3-fluorophenylmagnesium bromide prepared from    2-chloro-3-fluorobromobenzene and Mg turnings in Step 1.-   (R)-1-cyclohexyl-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol using    cyclohexylmagnesium bromide prepared from bromocyclohexane and Mg    turnings in Step 1.-   (S)-1-(3-ethylphenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-ethylphenyl-magnesium bromide prepared from    3-ethylbromobenzene and Mg turnings in Step 1.-   (S)-1-(3-bromophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 3-bromphenyl-magnesium iodide prepared from    3-bromo-1-iodobenzene and i-PrMgBr in Step 1.-   (S)-1-(2-bromo-5-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    using 2-bromo-5-fluorophenylmagnesium iodide prepared from    2-bromo-5-fluoro-1-iodobenzene and i-PrMgBr in Step 1.

Example 79N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide

Step 1. (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (7.75 g, 22.7 mmol)in MeOH (160 mL) was added NaBH₄ (6.9 g, 182 mmol) in portions such thatthe temperature remained below 40° C. After addition, the mixture wasstirred at rt for 3 h. TLC showed the start material had disappeared.The solvent was removed in vacuo and the residue was partitioned betweenwater and EtOAc. The organic layer was washed with H₂O and brine, driedover Na₂SO₄ and evaporated to give (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(4.35 g, 56%) which was used in the next step without purification. MS(E/Z): 344 (M+H⁺).

Step 2. (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate

To a stirred suspension of NaH (0.608 g, 15.2 mmol) in THF (100 mL) at0-5° C. was added dropwise a solution of (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)-piperidine-1-carboxylate(4.35 g, 12.68 mmol) in THF (30 mL). The reaction mixture was stirredfor an additional 1 h at rt. A solution of ethyl bromoacetate (2.52 g,15.2 mmol) in THF (30 mL) was added dropwise and the mixture wasrefluxed for 5 h. TLC showed the starting material had disappeared. Thereaction mixture was poured into sat'd aq NH₄Cl, extracted with EtOAc(3×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel to afford(R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate(4.368 g, 80%). ¹H NMR (400 MHz, CDCl₃): 0.861 (m, 2H), 1.25 (m, 6H),1.38&1.43 (s, 9H), 1.59-2.10 (m, 3H), 2.75 (m, 1H), 3.80 (s, 1H), 3.96(m, 2H), 4.18 (m, 2H), 4.62 (m, 1H), 7.12 (m, 1H), 7.33 (m, 2H); MS(E/Z): 430 (M+1)

Step 3. (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate(4.368 g, 10.2 mmol) in MeOH (85 mL) was added NaBH₄ (3.18 g, 81.5 mmol)in portions such that the temperature remained below 40° C. Afteraddition, the mixture was stirred at rt for 2˜3 h. TLC showed thestarting material had disappeared. The solvent was removed in vacuo andthe residue was partitioned between water and EtOAc. The organic layerwas washed with H₂O and brine, dried over Na₂SO₄ and evaporated to give(R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate(3.5 g, 89%). ¹H NMR (400 MHz, CDCl₃): 1.18 (m, 1H), 1.38-1.46 (s, 9H),1.65 (m, 1H), 1.85 (m, 2H), 2.66 (m, 1H), 3.25 (m, 1H), 3.38 (m, 2H),3.69 (m, 3H), 3.93 (m, 1H), 4.52 (m, 6H); MS (E/Z): 388 (M+1)

Step 4. (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)-piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)-piperidine-1-carboxylate(3.5 g, 9 mmol) in dry CH₂Cl₂ (50 mL) was added Et₃N (3.2 g, 4.2 mL, 27mmol, 4 eq) at 0˜−5° C. Then a solution of MsCl (1.23 g, 10.8 mmol, 1.2eq) in dry CH₂Cl₂ (20 mL) was added dropwise at the same temperature.After addition, the mixture was allowed to warm to rt gradually. TLCshowed the starting material had disappeared. Water (30 mL) was addedand the mixture was extracted with CH₂Cl₂ (3×20 mL). The combinedorganic layers were washed with 10% aq citric acid, sat'd aq NaHCO₃ andbrine, then dried over Na₂SO₄, filtered and concentrated to give3R-3-[(3-chloro-2-fluoro-phenyl)-(2-methanesulfonyloxy-ethoxy)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (4.13 g, 99%), which was used in the next stepwithout purification. ¹H NMR (400 MHz, CDCl₃): 1.35 (m, 4H), 1.46 (s,9H), 1.62 (m, 3H), 1.83 (m, 1H), 2.52-2.81 (m, 2H), 3.05 (m, 3H), 3.56(m, 2H), 3.92 (m, 1H), 4.30 (m, 2H), 4.48 (m, 1H), 7.13 (m, 1H), 7.28(m, 1H), 7.35 (m, 1H); MS (E/Z): 466 (M+)

Step 5. (R)-tert-butyl3-((2-azidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate

3R-3[(3-chloro-2-fluoro-phenyl)-(2-methanesulfonyloxy-ethoxy)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (4 g, 8.6 mmol) was dissolved in anhydrous DMF (30mL), solid NaN₃ (0.84 g, 12.9 mmol) was added and the reaction mixturewas heated at 80° C. overnight. The reaction mixture was cooled to rtand EtOAc (100 mL) was added. The mixture was washed with water (3×30mL), dried over Na₂SO₄ and evaporated. The residue was separated on asilica column to give (R)-tert-butyl3-((2-azidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate(2.6 g, 73%). ¹H NMR: (400 MHz, CDCl₃): 1.24 (m, 1H), 1.38&1.46 (s, 9H),1.67 (m, 3H), 1.83 (m, 1H), 2.58-2.81 (m, 2H), 3.32 (m, 2H), 3.45 (m,2H), 3.92 (m, 1H), 4.20 (m, 1H), 4.50 (m, 1H), 7.13 (t, 1H), 7.34 (m,2H), 8.02 (s, 1H);

Step 6. (R)-tert-butyl3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((2-azidoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate(2.6 g, 6.31 mmol) in EtOAc (50 mL) was added wetted Pd/C (0.1 g) andthe mixture was stirred overnight under a hydrogen atmosphere maintainedby a balloon. The reaction mixture was filtered through a pad of Celiteand the solvent was removed to give (R)-tert-butyl3-((2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylatewhich was submitted to reverse phase the preparative HPLC to give(R)-tert-butyl3-((S)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate(990 mg, 81%) and (R)-tert-butyl3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate(792 mg, 65%). MS (E/Z): 387 (M+H⁺).

Step 7. (R)-tert-butyl3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate(160 mg, 0.41 mmol) and Et₃N (1 mL) at 0° C. was added acetyl chloride(32.3 mg, 0.41 mmol). The mixture was allowed to warm to rt and stirredovernight. The mixture was concentrated in vacuo to give crude(R)-tert-butyl3-((R)-(2-acetamidoethoxy)-(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate(95 mg, 54%), which was used in the next step without furtherpurification. ¹H NMR: (400 MHz, CDCl₃): 1.20 (m, 1H), 1.40 (s, 9H), 1.70(m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, 1H), 4.42(m, 1H), 5.82 (m, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.34 (m, 1H); MS(E/Z): 429 (M+1). MS (E/Z): 429 (M+)

Step 8.N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide

(R)-tert-butyl3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate(95 mg, 1.88 mmol) was dissolved in 20% v/v TFA/CH₂Cl₂ (8 mL) at 0° C.,the mixture was allowed to warm to rt for 1 h and then concentrated invacuo to giveN-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide(63 mg, 87%), which was used without further purification. MS (E/Z): 329(M+)

terttertterttert

Example 81 (R)-3-((S)-1-(3-Chlorophenyl)-1,5-dimethoxypentyl)piperidine

Step 1. (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylate

To a mixture of (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate(0.1874 g, 0.45 mmol, 1.0 equiv) and 60% NaH in oil (0.345 g, 8.6 mmol,19 equiv) in THF (15 mL) was added iodomethane (1.195 g, 8.4 mmol, 18.5equiv). The resulting mixture was heated at 70° C. for 16 h and thenquenched with water, extracted with EtOAc and dried over Na₂SO₄. Afterthe solvent was removed, the crude (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylate(0.3175 g) was used in the next step without further purification. LC-MS(3 min) t_(R)=2.44 min m/z 450, 448 (M+Na⁺), 426 (M+H⁺), 340, 338, 294.

Step 2. (R)-3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine

A quarter of the (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylateobtained in Step 1 (ca. 75 mg, ca. 0.1 mmol) was dissolved in CH₃CN (30mL) and 2 N HCl (25 mL). The mixture was vigorously stirred at rt for 2d. The solvents were removed in vacuo to give the HCl salt of(R)-3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)-piperidine, which wasused without further purification. LC-MS (3 min) t_(R)=1.22 min, m/z328, 326 (M+H⁺).

Example 82(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1,5-dimethoxypentyl)piperidine

(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1,5-dimethoxypentyl)piperidinewas prepared using procedures analogous to those described in Example81, using (R)-tert-butyl3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylatein Step 1.

Example 831-((S)-4-(3-Chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-3-methylurea

Step 1. (R)-tert-butyl3-((S)-4-(methylaminocarbonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate

To a stirred mixture of the TFA salt of (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate(0.0388 g, 0.078 mmol, 1.0 equiv) in THF (5 mL) and CH₂Cl₂ (5 mL) at rtwere added of DIEA (0.7 mL) and p-nitrophenyl chloroformate (0.0350 g,0.17 mmol, 2.2 equiv). The mixture was stirred at rt for 3 h. One halfof the resulting solution was withdrawn and 33 wt % MeNH₂ in EtOH (1.5mL) was added. The resulting mixture was stirred at rt for 1 h. Thesolvents were removed in vacuo and the residue was purified byreversed-phase preparative HPLC (Phenomenex® Luna 5μ C18(2) 100 A,250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8 min andthen 90% CH₃CN/H₂O, 0.1% CF₃COOH over 7 min, flow rate 25 mL/min) togive (R)-tert-butyl3-((S)-4-(methylamino-carbonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate(0.0043 g). LC-MS (3 min) t_(R)=1.71 min, m/z 442, 440 (M+H⁺), 340.

Step 2.1-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-3-methylurea

A mixture of (R)-tert-butyl3-((S)-4-(methylaminocarbonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate,CH₃CN (20 mL) and 2 N aq HCl (15 mL) was vigorously stirred at rt for 2d. The solvents were removed in vacuo to give the HCl salt of1-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-3-methylurea,which was used without further purification. LC-MS (3 min) t_(R)=0.93min, m/z 342, 340 (M+H⁺).

Example 843-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-1,1-dimethylurea

3-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)-1,1-dimethylureawas prepared using procedures analogous to those described in Example83, using dimethylamine in Step 1.

Example 86

N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)methanesulfonamidewas prepared by reaction of (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylatewith methanesulfonyl chloride followed by Boc removal using theconditions described in Example 83 Step 2.

Example 87(S)-4-(Aminosulfonylamino)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol

Step 1. (R)-tert-butyl3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate

To a 50 mL round bottom flask were added the TFA salt of (R)-tert-butyl3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate(0.0803 g, 0.16 mmol, 1.0 equiv), sulfamide (0.2368 g, 2.46 mmol, 15equiv), 1,4-dioxane (5 mL) and DIEA (1 mL). The resulting mixture washeated at 110° C. for 2 h. After the solvents were removed in vacuo, theresidue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2)100 A, 250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 1.5 min, flow rate 25mL/min) to give 0.0438 g (59%) of (R)-tert-butyl3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate.LC-MS (3 min) t_(R)=1.74 min, m/z 486, 484 (MNa⁺), 362.

Step 2.(S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol

A mixture of (R)-tert-butyl3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate(0.0438 g, 0.095 mmol), CH₃CN (35 mL) and 2 N aq HCl (30 mL) wasvigorously stirred at rt for 24 h. The solvents were removed in vacuo togive the HCl salt of(S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol,which was used without further purification. LC-MS (3 min) t_(R)=0.93min, m/z 364, 362 (MH⁺), 285, 283.

Example 88 (R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid

Step 1. (R)-2-(Benzyloxymethyl)morpholine

To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9mmol) and NaOH (19.49 g, 487.2 mmol) in H₂O (46 mL) and MeOH (18 mL),there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) inportions. After addition the reaction mixture was stirred at 40° C. for2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0mmol) then toluene (70 mL) and stirred at 65° C. overnight. The mixturewas cooled, diluted with toluene (27 mL) and H₂O (92 mL). The toluenelayer was separated and the aqueous layer was extracted with CH₂Cl₂(2×50 mL). The combined organic layers were concentrated to give crude(R)-2-(benzyloxymethyl)morpholine (˜14 g), which was used withoutpurification. MS m/z 208 (M+H⁺).

Step 2. (R)-tert-Butyl 2-(benzyloxymethyl)morpholine-4-carboxylate

To a solution of crude (R)-2-(benzyloxymethyl)morpholine (˜14 g) inacetone (100 mL) and H₂O (30 mL) at 0° C., there was added K₂CO₃ (25.2g, 182.7 mmol), followed by (Boc)₂O (14.6 g, 67.0 mmol). The resultingsolution was warmed to rt, and stirred until no starting materialremained (˜30 min), acetone was removed under vacuum, and the aqueoussolution was extracted with CH₂Cl₂ (4×10 mL). The combined organiclayers were washed with H₂O (10 mL) and the solvent was removed. Theresidue was purified by flash column chromatography to give(R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44%over 2 steps). ¹H NMR (400 MHz, CDCl₃): 7.34 (m, 5H), 4.56 (s, 2H), 3.88(d, 2H), 3.82 (br, 1H), 3.40 (m, 1 H), 3.48 (m, 3H), 2.94 (m, 1H), 2.76(m, 1H), 1.44 (s, 9H); MS m/z 330 (M+Na⁺).

Step 3. (R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOHwas added Pd—C (wet, 3.6 g), and the resulting mixture was stirred at rtunder a H₂ balloon overnight. After filtration, the solvent was removedunder vacuum, and the residue was purified by flash columnchromatography to give (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99%) as a clear oil.¹H NMR (400 MHz, CDCl₃): 3.88 (d, 2H), 3.82 (br, 1H), 3.64 (d, 1H), 3.56(m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.90 (br, 1H), 1.44 (s, 9H); MS m/z218 (M+H⁺).

Step 4. (R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid

Sat'd aq NaHCO₃ (15 mL) was added to a solution of (R)-tert-butyl2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone(50 mL), stirred and maintained at 0° C. Solid NaBr (0.1 g, 1 mmol) andTEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g,10.0 mmol) was then added slowly within 20 min at 0° C. After additionthe mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL)was added, and the resulting solution was stirred at rt for 30 min,filtered through a pad of Celite, concentrated under vacuum, and treatedwith sat'd aq Na₂CO₃ (15 mL). The aqueous solution was washed with EtOAc(5 mL), acidified with 6 N HCl, and extracted with EtOAc (5×10 mL). Thecombined organic layers were dried over Na₂SO₄ and the solvent wasremoved to give (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid(1.07 g, 92%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 4.20 (br, 1H),4.12 (d, 1H), 4.02 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1 H), 3.04 (m, 2H),1.44 (s, 9H); MS m/z 232 (M+H⁺).

Example 89 6-Bromo-2-fluoro-3′-methyl-biphenyl

Step 1. Preparation of 1-Bromo-3-fluoro-2-iodo-benzene

To a solution of diisopropylamine (76 mL, 0.4 mol) in dry THF (664 mL)and n-hexane (220 mL) was added 2.5 M/L n-BuLi (160 mL. 0.4 mol)dropwise at −78° C. during a period of 1 h. The mixture was stirred for1 h at −78° C. Then a solution of 1-bromo-3-fluoro-benzene (69 g, 0.4mol) in dry THF (300 mL) at −78° C. was added to the above mixturedropwise. After stirring for an additional 1 h at −78° C., the mixturewas added a solution of iodine (101 g, 0.4 mol) in dry THF (400 mL)dropwise at −78° C. The temperature was raised from −78° C. to rt during2 h. After stirring for 18 h at rt, the mixture was concentrated invacuo to give crude product (120 g) which was distilled under reducedpressure to afford 1-bromo-3-fluoro-2-iodo-benzene (110 g). ¹H NMR (400MHz, DMSO): 7.24-7.19 (t, 1H), 7.38-7.32 (m, 1H), 7.55-7.53 (d, 1H).

Step 2. 6-Bromo-2-fluoro-3′-methyl-biphenyl

Pd(Ph₃P)₄ in a 500-mL round-bottom flask under N₂ atmosphore was treatedsequentially with a solution of 1-bromo-3-fluoro-2-iodo-benzene (30 g,0.1 mol) in toluene (250 mL), a solution of 2N aq Na₂CO₃ (200 mL) and3-methyl phenylboronic acid in ethanol (62 mL). This mixture was heatedat reflux under N₂ for 12 h, then cooled to rt. The mixture waspartitioned between water and EtOAc, the combined organic layers werewashed with brine, dried over MgSO₄, evaporated and purified by columnchromatography to give 6-bromo-2-fluoro-3′-methyl-biphenyl (12 g). ¹HNMR (400 MHz, CD₃OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, 1H).

Example 90 4-bromo-2-(trimethylsilyl)benzothiophene

Step 1. (3-bromophenyl)(2,2-diethoxyethyl)sulfane

To a stirred solution of 3-bromothiophenol (5.0 g, 26 mmol) in DMSO (40mL) was added a solution of KOH pellets (85% by wt, 2.15 g, 32 mmol) inwater (4 mL) followed by bromoacetaldehyde diethyl acetal (4.5 mL, 29mmol). The mixture was stirred at rt for 5 d, diluted with ether (300mL) and washed with water (3×100 mL). The combined water washes wereextracted with ether (100 mL). The combined ether extracts were washedwith brine (100 mL), dried over MgSO₄ and concentrated to afford(3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g, 100%) as a colorlessoil.

Step 2. 4-bromobenzothiophene

A stirred mixture of (3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g,26 mmol), polyphosphoric acid (20 mL) and chlorobenzene (30 mL) washeated at 130° C. for 1 h. The mixture was allowed to cool to rt and 1 Maq NaOH (100 mL) was added. The mixture was extracted with ether (2×100mL). The combined ether extracts were washed with water (25 m) and brine(25 mL) and dried over MgSO₄. Removal of the solvent left an oil (29.55g) which was chromatographed on a 120-g silica cartridge eluted withhexanes. Fractions containing the desired product were concentrated toafford an oil (3.33 g) which resubmitted to chromatography under thesame conditions to afford ˜80% pure 4-bromobenzothiophene (1.16 g, 20%).

Step 3. 4-bromo-2-(trimethylsilyl)benzothiophene

A stirred solution of ˜80% pure 4-bromobenzothiophene (580 mg, 2.7 mmol)and chlorotrimethylsilane (0.70 mL, 5.4 mmol) in dry THF (10 mL) wascooled to −70° C. and 2 M LDA in 1:1 THF/heptane (1.35 mL, 5.4 mmol) wasadded dropwise over 2 min. The mixture was stirred at −70° C. for 1.5 hand diluted with ether (80 mL) and 5% aq HCl (20 mL). The organic layerwas separated, washed with sat'd aq NaHCO₃ (20 mL) and dried over MgSO₄.Removal of the solvent left 4-bromo-2-(trimethylsilyl)benzothiophene(740 mg, 95%) as an amber oil.

Example 91 4-bromo-2-(trimethylsilyl)-benzofuran

4-Bromo-2-(trimethylsilyl)-benzofuran was made following proceduresanalogous to those described in Example 90, using 3-bromophenol in Step1.

Example 92 (S)-2-(trimethylsilyl)ethyl3-amino-5,5-dimethylhexyl(methyl)carbamate

Step 1. tert-Butyl (S)-1-(methylcarbamoyl)-3,3-dimethylbutylcarbamate

To a solution of(S)-2-(t-butoxyaminocarbonylamino)-4,4-dimethylpentanoic acid (1.0 g,4.08 mmol) and methylamine hydrochloride in DMF (10 mL) was added DIEA(2.1 mL, 12.2 mmol), followed by HBTU (1.55 g, 4.08 mmol). The resultingsolution was stirred at rt until no starting material remained (˜2 h).The solution was diluted with EtOAc (10 mL), washed with 1 N aq HCl (2×5mL), sat'd aq NaHCO₃ (10 mL) and brine, and dried over Na₂SO₄. Afterremoval of the solvent, the crude product was purified by flash columnchromatography to give tert-butyl(S)-1-(methylcarbamoyl)-3,3-dimethylbutyl carbamate (1.05 g, quant.) asa clear oil. MS m/z 281 (M+Na⁺).

Step 2. tert-Butyl (S)-4,4-dimethyl-1-(methylamino)pentan-2-ylcarbamate

To a solution of tert-butyl (S)-1-(methylcarbamoyl)-3,3-dimethylbutylcarbamate (1.05 g, 4.08 mmol) in toluene (10 mL) at 0° C., there wasadded Red-Al (65 wt % in toluene, 3.73 mL, 12.2 mmol) dropwise. Thesolution was warmed to rt slowly and stirred overnight. The reaction wasquenched with ice water, filtered through Celite, and solvent wasremoved to give tert-butyl(S)-4,4-dimethyl-1-(methylamino)pentan-2-ylcarbamate (0.79 g, 79%) as aclear oil. MS m/z 245 (M+H⁺).

Step 3. 2-(Trimethylsilyl)ethyl(S)-2-tert-butylcarboxylamino-4,4-dimethylpentylmethyl carbamate

To a solution of tert-butyl(S)-4,4-dimethyl-1-(methylamino)pentan-2-ylcarbamate (0.79 g, 3.24 mmol)in acetone (10 mL) and water (3 mL) was added K₂CO₃ (1.34 g, 9.72 mmol),followed by Teoc-OSu (0.84 g, 3.24 mmol). The resulting mixture wasstirred at rt until no starting material remained (˜1 h). Acetone wasremoved in vacuo, and the aqueous residue was extracted with CH₂Cl₂ (4×5mL), the combined organic layers were concentrated, and the cruderesidue was purified by flash column chromatography to give2-(trimethylsilyl)ethyl(S)-2-tert-butylcarboxylamino-4,4-dimethylpentylmethyl carbamate (0.74g, 59%) as a clear oil. MS m/z 389 (M+H⁺).

Step 4. (S)-2-(trimethylsilyl)ethyl3-amino-5,5-dimethylhexyl(methyl)carbamate

To a solution of 2-(trimethylsilyl)ethyl(S)-2-tert-butylcarboxylamino-4,4-dimethylpentylmethyl carbamate (0.74g, 1.90 mmol) in ether (7 mL) was added a solution of p-toluenesulfonicacid (0.37 g, 1.92 mmol) in 1.5 mL of ethanol (1.5 mL). Transfer of thep-toluenesulfonic acid was completed with the aid of ether (1 mL). Thesolution was placed on a rotary evaporator and the ether removed underreduced pressure at rt. Then, with continuing evacuation, the bathtemperature was raised to 60-65° C. for 20 min, during which gasevolution was evident. The solid residue of the toluensulfonate salt of(S)-2-(trimethylsilyl)ethyl 3-amino-5,5-dimethylhexyl(methyl)carbamatewas used without purification in the next step. MS m/z 289 (M+H⁺).

Example 93

The following compounds were prepared using procedures analogous tothose described in Example 92:

-   2-(trimethylsilyl)ethyl (S)-2-amino-4-methylpentylmethylcarbamate-   2-(trimethylsilyl)ethyl (S)-2-aminopropylmethylcarbamate-   2-(trimethylsilyl)ethyl    2-amino-3-(tetrahydro-2H-pyran-4-yl)propyl(methyl)carbamate-   2-(trimethylsilyl)ethyl    2-amino-5,5,5-trifluoro-4-methylpentyl(methyl)carbamate-   2-(trimethylsilyl)ethyl    2-amino-4,4,4-trifluorobutyl(methyl)carbamate-   (S)-2-(trimethylsilyl)ethyl    2-amino-3-cyclopropylpropyl(methyl)carbamate-   2-(trimethylsilyl)ethyl 2-amino-2-methylpropyl(methyl)carbamate.-   (R)-2-(trimethylsilyl)ethyl    1-amino-3-tert-butoxypropan-2-ylcarbamate

Example 94 2-(Trimethylsilyl)ethyl(2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropylmethylcarbamate

Step 1. tert-Butyl (S)-1-(methylcarbamoyl)-2-hydroxyethylcarbamate

To a solution of L-N-Boc-serine (6.33 g, 30.8 mmol) and methylaminehydrochloride (3.12 g, 46.2 mmol) in DMF (30 mL) was added DIEA (16.0mL, 92.4 mmol), followed by HBTU (11.90 g, 31.0 mmol). The resultingsolution was stirred at rt until no starting material remained (˜2 h).The solution was diluted with EtOAc (30 mL), washed with 1 N aq HCl(2×10 mL), sat'd aq NaHCO₃ (15 mL) and brine, and dried over Na₂SO₄.After removal of the solvent, the crude product was purified by flashcolumn chromatography to give tert-butyl(S)-1-(methylcarbamoyl)-2-hydroxyethyl carbamate (6.93 g, quant.) as aclear oil. MS m/z 219 (M+H⁺).

Step 2. tert-Butyl (R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate

To a solution of tert-butyl (S)-1-(methylcarbamoyl)-2-hydroxyethylcarbamate (6.93 g, 30.8 mmol) in toluene (50 mL) at 0° C. was addeddropwise Red-Al (65 wt % in toluene, 28.3 mL, 92.4 mmol) dropwise. Thesolution was warmed to rt slowly and stirred overnight. The reaction wasquenched with ice water, filtered through Celite, and solvent wasremoved to give crude tert-butyl(R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate (˜13 g) which used fornext step without purification. MS m/z 205 (M+H⁺).

Step 3.(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol

To a solution of crude tert-butyl(R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate in acetone (30 mL) andwater (10 mL), there was added K₂CO₃ (12.8 g, 92.4 mmol), followed byTeoc-OSu (8.0 g, 30.8 mmol). The resulting mixture was stirred at rtuntil no starting material remained (˜1 h). Acetone was removed undervacuum and the aqueous residue was extracted with CH₂Cl₂ (4×15 mL). Thecombined organic layers were concentrated and the crude residue waspurified by flash column chromatography to give(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol(2.12 g, 20% steps). ¹H NMR (400 MHz, CDCl₃): 5.08 (br, 1H), 4.14 (m,2H), 3.66-3.42 (m, 4H), 3.02 (m, 1H), 2.90 (s, 3H), 1.40 (S, 9H), 0.98(m, 2H), 0.02 (s, 9H); MS m/z 349 (M+H⁺).

Step 4. (2-(trimethylsilyl)ethyl)(R)-2-(t-butoxycarbonylamino)-2-formylethylmethylcarbamate

To a solution of tert-butyl(R)-3-hydroxy-1-(methyl-N-Teoc-amino)propan-2-ylcarbamate (0.97 g, 2.79mmol) in 1,2-dichloroethane (10 mL) was added Dess-Martin periodinane(1.76 g, 3.63 mmol), and the resulting mixture was heated in a CEMmicrowave reactor at 70° C. for 3 min. The completion of the reactionwas confirmed by TLC. The mixture was diluted with ether (20 mL), washedwith 1 N aq NaOH (2×10 mL) and brine, and dried over Na₂SO₄. The solventwas removed to give a crude (2-(trimethylsilyl)ethyl)(R)-2-(t-butoxycarbonylamino)-2-formylethylmethylcarbamate (0.71 g,73%), which was used without purification.

Step 5. 2-(Trimethylsilyl)ethyl(2R,3R)-2-N-tert-butylcarboxyamino-3-cyclohexyl-3-hydroxypropylmethylcarbamate

To a solution of above crude (2-(trimethylsilyl)ethyl)(R)-2-(t-butoxycarbonylamino)-2-formylethylmethylcarbamate (0.71 g, 2.05mmol) in toluene (6 mL) at −78° C. was added cyclohexylmagnesiumchloride (2 M in ether, 5.13 mL) dropwise. The resulting solution wasstirred at −78° C. for 1 h, allowed to warm slowly to rt, and quenchedwith sat'd aq NH₄Cl (5 mL). The organic layer was separated, and aqueouslayer was extracted with ether (2×5 mL). The combined organic layerswere concentrated in vacuo, and the residue was purified by flash columnchromatography to give(1R,2R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol(209.7 mg, 24%). ¹H NMR (400 MHz, CDCl₃): 4.94 (d, 1H), 4.16 (m, 2H),3.80 (m, 1H), 3.78 (m, 1H), 3.04 (m, 1H), 2.88 (m, 1H), 2.86 (s, 3H),2.10 (m, 1H), 1.64 (m, 4H), 1.42 (m, 1H), 1.40 (s, 9H), 1.28-1.02 (m,4H), 0.98 (m, 2H), 0.82 (m, 4H), 0.02 (s, 9H); MS m/z 431 (M+H⁺).

Step 6. 2-(Trimethylsilyl)ethyl(2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropyl methyl carbamate

To a solution of 2-(trimethylsilyl)ethyl(2R,3R)-2-N-tert-butylcarboxyamino-3-cyclohexyl-3-hydroxypropylmethylcarbamate(220 mg, 0.51 mmol) in ether (2 mL) was added a solution ofp-toluenesulfonic acid (99 mg, 0.52 mmol) in 1.0 mL of ethanol. Transferof the p-toluene-sulfonic acid was completed with the aid of ether (0.5mL). The solution was placed on a rotary evaporator and the etherremoved under reduced pressure at rt. Then, with continuing evacuation,the bath temperature was raised to 60-65° C. for 20 min, during whichgas evolution was evident. The crude p-toluenesulfonic acid salt of2-(trimethylsilyl)ethyl (2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropylmethyl carbamate obtained was used without purification. MS m/z 331(M+H⁺).

Example 95 2-(Trimethylsilyl)ethyl(2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropylmethylcarbamate

Step 1.(R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-1-one

To a solution of(1R,2R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol(0.76 g, 1.76 mmol) in 1,2-dichloroethane (4 mL) was added Dess-Martinperiodinane (1.05 g, 2.29 mmol), and the resulting mixture was heated ina CEM microwave reactor at 70° C. for 3 min. Completion of reaction wasconfirmed by TLC. The mixture was diluted with ether (20 mL), washedwith 1 N aq NaOH (2×10 mL) and brine, dried over Na₂SO₄, andconcentrated to give crude(R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-one(0.74 g), which was used without purification.

Step 2. 2-(Trimethylsilyl)ethyl(2R,3S)-2-N-tert-butylcarboxyamino-3-cyclohexyl-3-hydroxypropylmethylcarbamate

To a solution of(R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-one(0.74 g) in methanol (4 mL) at 0° C., was added NaBH₄ (0.11 g) in oneportion. The resulting solution was stirred at 0° C. until no startingmaterial remained (˜20 min) and the reaction was quenched with icewater. Methanol was removed in vacuo and the residue was distributedbetween ether (10 mL) and water (10 mL). The aqueous layer was extractedwith ether (2×5 mL) and the combined organic layers were concentrated.The residue was purified by flash column chromatography to give2-(trimethylsilyl)ethyl (2R,3S)-2-N-tert-butylcarboxyamino-3-cyclohexyl-3-hydroxypropylmethyl carbamate (0.21 g, 22% twosteps). ¹H NMR (400 MHz, CDCl₃): 4.96 (d, 1H), 4.12 (m, 2H), 3.88 (m,1H), 3.64 (m, 1H), 3.40-3.14 (m, 2H), 2.86 (s, 3H), 1.94 (m, 1H),1.80-1.50 (m, 4H), 1.40 (sm, 10H), 1.18 (m, 5H), 0.98 (m, 2H), 0.02 (s,9H); MS m/z 431 (M+H⁺).

Step 3. 2-(Trimethylsilyl)ethyl(2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropyl methylcarbamate

To a solution of 2-(trimethylsilyl)ethyl(2R,3S)-2-N-tert-butylcarboxyamino-3-cyclohexyl-3-hydroxypropylmethylcarbamate(210 mg, 0.49 mmol) in ether (2 mL) was added a solution ofp-toluenesulfonic acid (95.0 mg, 0.50 mmol) in 1.0 mL of ethanol.Transfer of the p-toluenesulfonic acid was completed with the aid ofether (0.5 mL). The solution was placed on a rotary evaporator and theether removed under reduced pressure at rt. Then, with continuingevacuation, the bath temperature was raised to 60-65° C. for 20 min,during which gas evolution was evident. The crude p-toluenesulfonatesalt of 2-(trimethylsilyl)ethyl(2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropyl methylcarbamate was usedwithout further purification. MS m/z 331 (M+H⁺).

Example 96(2R)-2-amino-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propane

Step 1. (2-(Trimethylsilyl)ethyl)(R)-2-amino-3-hydroxypropylmethylcarbamate

To a solution of(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-1-ol(0.55 g, 1.58 mmol) in ether (5 mL) was added a solution ofp-toluenesulfonic acid (0.31 g, 1.60 mmol) in ethanol (2 mL). Transferof the p-toluenesulfonic acid was completed with the aid of ether (1mL). The solution was placed on a rotary evaporator and the etherremoved under vacuum at rt. Then, with continuing evacuation, the bathtemperature was raised to 60-65° C. for 30 min, during which gasevolution was evident. The solid residue was dissolved in 1 N aq NaOHsolution (5 mL) and extracted with CH₂Cl₂ (4×5 mL). The combined organiclayers were washed with brine and dried over Na₂SO₄. Solvent was removedin vacuo to give (2-(trimethylsilyl)ethyl)(R)-2-amino-3-hydroxypropyl-methylcarbamate (0.35 g, 90%) as a freeamine, which was without purification. MS m/z 249 (M+H⁺).

Step 2.(2R)-2-amino-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propane

To a solution of above (2-(trimethylsilyl)ethyl)(R)-2-amino-3-hydroxypropylmethyl carbamate (0.35 g, 1.41 mmol) inanhydrous CH₂Cl₂ (4 mL) at 0° C. was added triethylamine (1.0 mL),followed by trimethylsilyl chloride (0.54 mL, 4.23 mmol). The resultingsolution was warmed to rt slowly and stirred at rt until no startingmaterial remained (˜1 h). Solvent was removed in vacuo. The residue wasredissolved in CH₂Cl₂ (2 mL) and the solvent was again removed in vacuoto give(2R)-2-amino-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propaneas a clear oil which was used for the next reaction withoutpurification. MS m/z 321 (M+H⁺).

Example 97 2-(Trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate

Step 1. 1-((1-Tosylaziridin-2-yl)methyl)cyclohexanol

A flame-dried 100 mL three-necked flask was purged with N₂, and chargedwith Cu(OTf)₂ (95 mg, 0.26 mmol), 1-allylcyclohexanol (960 mg, 9.86mmol) and acetonitrile (HPLC grade). Solid[N-(p-Toluenesulfonyl)imino]phenyliodinane (PhINTs, prepared asdescribed in Inorgania Chimica Acta 2003, 342, 301-304, 1.97 g, 5.28mmol) was added in a single portion and the mixture was stirred at rtuntil all PhINTs had dissolved (within 5 to 30 min). The solvent wasremoved and the residue was chromatographied on silica gel eluted withhexane/EtOAc to give 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (217mg, 13%). MS m/z 310 (M+H⁺).

Step 2. 1-(3-(Methylamino)-2-(tosylamino)propyl)cyclohexanol

A solution of 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (270 mg, 0.87mmol) and methylamine in MeOH was stirred at rt for 4 h and concentratedto give 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol. The crudeproduct was used in the next step without purification. MS m/z 341(M+H⁺).

Step 3. 2-(Trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-(tosylamino)propylmethylcarbamate

To a solution of 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol in3:1 THF/H₂O v/v (4 mL) was added K₂CO₃ (240 mg, 1.74 mmol), followed byTeoc-OSu (248 mg, 0.96 mmol). The resulting solution was stirred at rtfor 30 min and the organic solvent was removed under reduced pressure.The residue was extracted with EtOAc (2×). The combined organic phaseswere washed with brine, dried, filtered and concentrated under vacuum.The residue was chromatographied on silica gel to give2-(trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-(tosylamino)propylmethylcarbamate (300 mg, 74%for two steps). MS m/z 469 (M+H⁺).

Step 4. 2-(Trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate

Sodium naphthalenide solution was prepared as described in J. Org. Chem.1989, 54, 1548-1562. To a well stirred, cooled (−70° C.) solution of2-(trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-(tosylamino)propylmethyl carbamate (113 mg,0.233 mmol) in anhydrous DME (20 mL) under a N₂ atmosphere was addeddropwise freshly prepared sodium naphthalenide solution until a lightgreen color persisted. The reaction was quenched with water, dilutedwith EtOAc and washed with 1 N aq The acidic aqueous phase was basifiedwith K₂CO₃, and extracted with EtOAc (2×). The combined organic phaseswere dried over anhydrous Na₂SO₄, filtered and evaporated under reducedpressure to give pure 2-(trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate (36.6 mg, 43.6%).MS m/z 331 (M+H⁺).

Example 981-(2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(p-nitrophenoxycarbonylamino)propyl)-1-(trimethylsilyloxy)cyclohexane

Step 1. 1-(3-Amino-2-(tosylamino)propyl)cyclohexanol

To a solution of 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (107 mg,0.346 mmol) in MeOH (2 mL) was added satd aq ammonia (2 mL). Theresulting solution was stirred at rt for 4 h and concentrated to give1-(3-amino-2-(tosylamino)propyl)cyclohexanol which was used for the nextstep without purification. MS m/z 327 (M+H⁺).

Step 2. tert-Butyl 3-(1-hydroxycyclohexyl)-2-(tosylamino)propylcarbamate

To a solution of above 1-(3-amino-2-(tosylamino)propyl)cyclohexanol in3:1 THF/H₂O v/v (4 mL) was added K₂CO₃ (143 mg, 1.038 mmol), followed byBoc₂O (80 mg, 0.367 mmol). The resulting solution was stirred at rt for30 min and the organic solvent was removed under reduced pressure. Theaqueous residue was extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried, filtered and concentrated invacuo. The residue was chromatographed on silica gel to give tert-butyl3-(1-hydroxycyclohexyl)-2-(tosylamino)-propylcarbamate (138 mg, 91% fortwo steps). MS m/z 449 (M+Na⁺).

Step 3. tert-Butyl3-(1-hydroxycyclohexyl)-2-(N-methyl-N-tosylamino)propyl carbamate

To a solution of tert-butyl3-(1-hydroxycyclohexyl)-2-(tosylamino)propylcarbamate (115 mg, 0.27mmol) in dry DMF (2 mL) was added K₂CO₃ (110 mg, 0.80 mmol). The mixturewas stirred at rt for 30 min before MeI (57.5 mg, 25 μL, 0.41 mmol) wasadded. The mixture was stirred for 1 h and the organic solvent wasremoved under vacuum. The residue was partitioned between EtOAc and H₂O.The separated aqueous phase was extracted with EtOAc (2×) and thecombined organic phases were washed with brine and dried over Na₂SO₄.Removal of the solvent under reduced pressure gave crude tert-butyl3-(1-hydroxycyclohexyl)-2-(N-methyl-N-tosylamino)propyl carbamate (117mg), which was used without further purification. MS m/z 463 (M+Na⁺).

Step 4. tert-Butyl3-(1-hydroxycyclohexyl)-2-(methylamino)propylcarbamate

To a well-stirred, cooled (−70° C.) solution of crude tert-butyl3-(1-hydroxycyclohexyl)-2-(N-methyl-N-tosylamino)propyl carbamate (117mg, ca. 0.27 mmol) in anhydrous DME (20 mL) under N₂ atmosphere wasadded freshly prepared sodium naphthalenide solution dropwise until alight green color persisted. The reaction was quenched with water,diluted with EtOAc, washed with H₂O and brine successively, and driedover Na₂SO₄. Removal of the solvent afforded a mixture of tert-butyl3-(1-hydroxycyclohexyl)-2-(methylamino)propylcarbamate and naphthalenewhich was used for next step without further purification. MS m/z 287(M+H⁺).

Step 5.1-(3-(t-butoxycarbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol

To a solution of above mixture of tert-butyl3-(1-hydroxycyclohexyl)-2-(methylamino)-propylcarbamate and naphthalenein 3:1 THF/H₂O v/v (4 mL) was added K₂CO₃ (100 mg, 0.72 mmol), followedby Teoc-OSu (70 mg, 0.27 mmol). The resulting solution was stirred at rtfor 30 min and the organic solvent was removed under reduced pressure.The residue was extracted with EtOAc (2×). The combined organic phaseswere washed with brine, dried, filtered, and concentrated under vacuum.The residue was chromatographed on silica gel to give1-(3-(t-butoxycarbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol(100 mg, 86% for three steps). MS m/z 453 (M+Na⁺).

Step 6.1-(3-Amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol

A solution of p-TsOH.H₂O (25 mg) in ethanol (0.5 mL) was added to1-(3-(t-butoxy-carbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol(50 mg, 0.12 mmol) dissolved in ether (12 mL). The transfer wascompleted with additional ether (2 mL). The resulting solution wasevaporated under reduced pressure at rt to remove Et₂O and heated at60-65° C. for 20 min under reduced pressure to remove ethanol. Theresidue was dissolved in MeOH and aqueous K₂CO₃ was added. The mixturewas evaporated and extracted with EtOAc (3×). The combined organicphases were dried over Na₂SO₄, filtered and evaporated to give1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol(43 mg, 89%). MS m/z 453 (M+Na⁺).

Step 7.1-(2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(p-nitrophenoxycarbonyl-amino)propyl)-1-(trimethylsilyloxy)cyclohexane

To a solution of1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-propyl)cyclohexanol(21 mg, 0.064 mmol) in CH₂Cl₂ (2 mL) were added Et₃N (0.2 mL) andMe₃SiCl (13.9 mg, 16 μL, 0.13 mmol). The resulting solution was stirredfor 1 h and evaporated under vacuum. The residue was dissolved in CH₂Cl₂(2 mL) and pyridine (0.05 mL) was added, followed by 4-nitrophenylchloroformate (15 mg, 0.077 mmol). The mixture was stirred for 30 min toafford a solution of1-(2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(p-nitrophenoxycarbonylamino)propyl)-1-(trimethylsilyloxy)cyclohexanewhich was used directly without isolation.

Example 99 (2-(Trimethylsilyl)ethyl)(S)-2-amino-3-(4-methylcyclohexyl)propylmethylcarbamate

Step 1. (S)-2-amino-3-(4-methylcyclohexyl)propanoic acid

A 250 mL Parr shaker vessel was charged with of 4-methylphenylalanine(1.0 g, 5.6 mmol), PtO₂ (63 mg, 0.28 mmol, 5 mol %) and 1:1 TFA/water(10 mL). The vessel was placed in a Parr hydrogenation shaker andpressurized/evacuated with hydrogen gas (3×), then pressurized to 50psi. The reaction vessel was shaken for 2 d, then carefully vented.Analysis of the mixture by LC-MS showed no remaining starting materialand two peaks with the desired mass, consistent with a ca 1:1 mixture ofcis:trans isomers. The contents were filtered through a pad of Celiteand the spent catalyst washed with additional water. The clear filtratewas evaporated to afford the TFA salt of(S)-2-amino-3-(4-methylcyclohexyl)propanoic acid, which used directly inthe next step.

Step 2. (S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoicacid

The crude TFA salt of (S)-2-amino-3-(4-methylcyclohexyl)propanoic acidfrom Step 1 was dissolved in dioxane (20 mL) and 0.67 M aq NaOH (30 mL).The pH of the solution was raised to >14 by addition of solid KOH, thendi-tert-butyl dicarbonate (3.03 g, 13.9 mmol, 1.05 equiv) was added.After stirring for 1 h, LC-MS analysis showed ca. 80% conversion to thedesired carbamate. Addition di-tert-butyl dicarbonate (600 mg) was addedand the mixture stirred overnight. After this time all the free aminehad been consumed. The mixture was cooled to 0° C. and solution pHlowered to <4 by addition of sat'd aq citric acid. Most of the dioxanewas removed using a rotary evaporator and the aqueous residue wasextracted with EtOAc (5×25 mL). The combined organic extracts were driedover Na₂SO₄, filtered and evaporated to yield(S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoic acid asa tacky solid.

Step 3. tert-Butyl(S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)ethylcarbamate

A mixture of(S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoic acid(2.080 g, 7.29 mmol, 1.0 equiv), EDC.HCl (3.308 g, 2.37 equiv), HOBt(1.752 g, 1.78 equiv), DIEA (7.6 mL, 6 equiv) and 33% wt. methylamine inEtOH (2.771 g, 4 equiv) in CH₂Cl₂ (80 mL) was stirred at rt for 21 h.The solvents were removed in vacuo and 1 N aq HCl (200 mL) was added.The mixture was extracted with EtOAc (3×). The combined organic extractswere washed with brine and dried over Na₂SO₄. After the solvents wereremoved in vacuo, the residue was purified by reversed-phase HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOHover 3.5 min, flow rate 25 mL/min) to give tert-butyl(S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)-ethylcarbamate (1.0167 g,47%). LC-MS (3 min) t_(R)=1.72 min, m/z 321 (M+Na⁺), 243, 199; ¹H NMR(400 MHz, CDCl₃) δ 6.27 (br s, 1H), 4.91 (br s, 1H), 4.11-4.07 (m, 1H),2.802, 2.798 (d, J=4.8 Hz, 3H), 1.85-1.20 (m, 21H), 0.886, 0.851 (d,J=6.4 Hz, 3H).

Step 4. tert-Butyl(S)-1-(methylamino)-3-(4-methylcyclohexyl)propan-2-ylcarbamate

To a solution of tert-butyl(S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)-ethylcarbamate (1.0075 g,3.38 mmol, 1.0 equiv) in THF (40 mL) at 0° C. under N₂ was added 1.0 MLiAlH₄ in THF (7 mL, 7 mmol, 2.1 equiv). The mixture was stirred at rtfor 19 h and sodium sulfate decahydrate (6.45 g, 20 mmol) was addedcarefully to quench excess LiAlH₄. The mixture was filtered and thesolid was washed with ether. After the solvents were removed in vacuo,the crude product (1.04 g) was used in the next step without furtherpurification. LC-MS (3 min) t_(R)=1.37 min, m/z 285 (MH⁺), 229.

Step 5. 2-(Trimethylsilyl)ethyl(S)-2-amino-3-(4-methylcyclohexyl)-propylmethylcarbamate

A mixture of tert-butyl(S)-1-(methylamino)-3-(4-methylcyclohexyl)propan-2-ylcarbamate (1.04 g),obtained as described above, K₂CO₃ (2.17 g, 15.7 mmol, 4.65 equiv),Teoc-OSu (1.53 g, 5.90 mmol, 1.75 equiv), H₂O (20 mL) and CH₂Cl₂ (100mL) was stirred vigorously at rt for 4 h. The mixture was diluted brineand extracted with CH₂Cl₂ (3×). The combined organic extracts were driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (40 g silica gel cartridge, 0%→30% EtOAc/hexanesover 30 min, flow rate 40 mL/min) to give (0.534 g, 37% in two steps) ofN-Boc-N′-Teoc protected diamine which was used in the next step. LC-MSt_(R)=2.60 min in 3 min chromatography, m/z 451 (MNa⁺), 301.

A mixture of N-Boc-N′-Teoc protected diamine (0.534 g, 1.25 mmol, 1.0equiv) and TsOH.H₂O (0.234 g, 1.23 mmol, 0.99 equiv) in ethanol washeated with a 60° C. water bath and the solvent was removed underreduced pressure. 1 N aq NaOH (3 mL) was added to the residue. Afterwater was removed in vacuo, the residue was extracted with CH₂Cl₂. Theorganic extract was dried over Na₂SO₄, filtered through an HPLC filterand dried in vacuo to give of 2-(trimethylsilyl)ethyl(S)-2-amino-3-(4-methylcyclohexyl)-propylmethylcarbamate (0.3492 g,85%). LC-MS t_(R)=1.59 min in 3 min chromatography, m/z 329 (MH⁺), 301.

Example 1002-(2-(trimethylsilyl)ethoxycarbonylamino)-1-(3,3-difluorocyclobutyl)-3-(N-(t-butoxycarbonyl)-N-methylamino)-propane

Step 1. Diisopropyl-3,3-Dimethoxycyclobutane-1,1-Dicarboxylate

Following the procedure of Pigou and Scheisser (J. Org. Chem. 1988, 53,3841), a 500 mL, 3-neck flask, fitted with a reflux condenser andthermocouple, was charged with NaH (60% in mineral oil, 4 g, 0.210 mol).DMF (100 mL) was added via syringe and the slurry was stirred under N₂.Diisopropyl malonate was added at a rate so that the internaltemperature did not rise above 70° C. After the H₂ evolution had ceased,the flask was briefly opened and 1,3-dibromo-2,2-dimethoxypropane wasadded. The bath temperature was raised to 145° C. The reaction mixturewas maintained at this temperature for 48 h. After this time the darkbrown mixture was allowed to cool to rt. Water (50 mL) was added and thesolvents were removed in vacuo. The residue was partitioned betweenether (200 mL) and sat'd aq NH₄Cl (200 mL) and the mixture filteredthrough a pad of Celite to remove solid impurities. The aqueous layerwas extracted with ether (2×100 mL). The combined ether extracts werewashed with brine, dried over Na₂SO₄, filtered and evaporated. Flashchromatography (SiO₂, 0-25% EtOAc in hexanes) gave semi-purediisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g), whichwas used in the next step.

Step 2. 3-Oxocylobutanecarboxylic Acid

Diisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g) wasadded to 75 mL of 20% aq HCl. The mixture was heated to reflux for 60 h.The brown solution was cooled to rt and satd with NaCl. The aqueouslayer was extracted with ether (7×75 mL) and stripped to yield3-oxocylobutanecarboxylic acid (12.2 g) as a brown oil.

Step 3. Butyl 3-oxocylobutanecarboxylate

3-Oxocylobutanecarboxylic acid (12.2 g, <0.107 mol, 1.0 equiv) and DMAP(10.5 g, 0.856 mol) were dissolved in butanol (100 mL) and the mixturecooled to 0° C. DCC (24.2 g, 0.118 mol, 1.2 equiv) was added as a solid.The mixture was allowed to stir for 15 h with concomitant warming to rt.The mixture was filtered through a pad of Celite. The filter cake waswashed with hexanes. The filtrate was washed with 1.0 M aq HCl, sat'd aqNaHCO₃ and brine. Evaporation of the solvent afforded a brown oil. Thiswas purified by flash chromatography (SiO₂, 0-20% EtOAc). The fractionswhich stained with 2,4-dinitrophenylhydrazine on tlc were pooled andevaporated to yield a pale yellow oil which was dissolved in hexane andfiltered through Celite. The filtrate was evaporated to yield butyl3-oxocylobutanecarboxylate (4.97 g) as a clear oil.

Step 4. Butyl 3,3-difluorocylobutanecarboxylate

The ester (4.97 g, 0.0292 mol, 1.0 equiv) was dissolved in CH₂Cl₂ andcooled to 0° C. DAST (11.5 mL, 0.0876 mol, 3.0 equiv) was added viasyringe and the mixture was stirred overnight with warming to rt. TLCanalysis showed no spots which stain with 2,4-dinitrophenylhydrazine.The mixture was cooled to 0° C. and sat'd NaHCO₃ was added, followed by1.0 M aq NaOH till the pH>14. The layers were separated and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were driedover Na₂SO₄ and evaporated to leave butyl3,3-difluorocylobutanecarboxylate (5.5 g) as a brown oil, which was usedin the next step.

Step 5. (3,3-Difluorocylobutyl)methanol

A three-neck, 500 mL flask was charged with LiAlH₄ (2.4 g, 63 mmol, 2.2equiv) and ether (140 mL) and cooled to −40° C. A solution of butyl3,3-difluorocylobutanecarboxylate (5.5 g, 28.6 mmol, 1.0 equiv) in ether(20 mL) was added dropwise over a 20 min. The excess LiAlH₄ was quenchedby sequential addition of water (2.5 mL), 10% aq NaOH (2.5 mL) andcelite (10 g). The mixture was stirred for 30 min and diluted with EtOAc(100 mL). The mixture was filtered through a pad of celite. The filtratewas washed with brine, dried over Na₂SO₄, filtered and evaporated. Thisafforded (3,3-difluorocylobutyl)methanol (2.4 g) contaminated with ca10% butanol. This crude material was used in the subsequent step.

Step 6. (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate

A round bottom flask was charged with (3,3-difluorocylobutyl)methanol(1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g,8.6 mmol, 1.05 equiv) and CH₂Cl₂ (50 mL). The mixture was cooled to 0°C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was addedvia syringe. The mixture stirred for 12 h with warming to rt. After thistime 1.0 M aq HCl (50 mL) was added. The layers were separated, theorganic layer was extracted with CH₂Cl₂ (50 mL) and the combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andevaporated. The compound was purified by flash chromatography on silica,eluting with 0-30% EtOAc in hexanes. This afforded(3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) asan off white solid.

Step 7. Diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate

(3,3-Difluorocyclobutyl)methyl 4-bromobenzenesulfonate (500 mg, 1.47mmol) and NaI (220 mg, 1.47 mmol, 1.0 equiv) were stirred in dry DMF (4mL). In a separate 3-neck, 100 mL flask NaH (60 wt % in oil, 352 mg,8.82 mmol, 6 equiv) was slurried in dry DMF (20 mL). The flask wascooled to 0° C. and diethyl-2-acetamidomalonate was added via syringe.After gas evolution ceased, the solution of the(3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate and NaI In DMFwas added. The resulting solution was heated to 45° C. for 17 h. Afterthis time no remaining brosylate or iodide was observed by TLC andLC-MS. The mixture was quenched by dropwise addition of water (10 mL)and the DMF was removed in vacuo. The residue was partitioned betweenether and water and the layers separated. The aqueous layer wasextracted with additional ether and the combined organic layers werewashed with brine. The residue was evaporated and the desired productwas purified by flash chromatography on silica, eluting with 0 to 50%EtOAc in hexanes. The fractions were stained with ceric ammoniummolybdate; the desired product is contained in the second spot. Thisafforded diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate(474 mg, 99%).

Step 8. 2-Amino-3-(3,3-difluorocyclobutyl)propanoic acid, HCl salt

Diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate (474 mg,1.47 mmol) was slurried in 18% HCl (30 mL) and the mixture was heated toreflux for 8 h. After this time LC-MS showed complete conversion to thedesired product. The solvent was removed to leave the hydrochloride of2-amino-3-(3,3-difluorocyclobutyl)propanoic acid as an off-white solidwhich was used directly in the next step. A quantitative yield wasassumed.

Step 9.2-(2-(Trimethylsilyl)ethoxycarbonyl)amino-3-(3,3-difluorocyclobutyl)propanoicacid

The crude HCl salt 2-amino-3-(3,3-difluorocyclobutyl)propanoic acid(0.74 mmol) was dissolved in dioxane (5 mL) and 1.0 M aq NaOH 2.5 mL).Teoc-OSu (213 mg, 0.820 mmol, 1.1 equiv) was added and the mixture wasstirred overnight at rt. The solvent was removed and the residue wastaken up in water (˜5 mL). Citric acid (10% weight solution) was addedtill pH<4 and the mixture was extracted with EtOAc. The organic extractwas dried over Na₂SO₄, filtered and solvent was removed to yield2-(2-(trimethylsilyl)ethoxycarbonyl)amino-3-(3,3-difluorocyclobutyl)propanoicacid (273 mg) as a white foam. ¹H and ¹⁹F NMR were consistent with thedesired product contaminated with Teoc-OSu.

Step 10. 2-(Trimethylsilyl)ethyl3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate

Crude2-(2-(trimethylsilyl)ethoxycarbonyl)amino-3-(3,3-difluorocyclobutyl)propanoicacid (273 mg, 0.844 mmol) was dissolved in THF (5 mL) and the solutionwas cooled to −10° C. N-methylmorpholine (95 mg, 0.929 mmol, 1.1 equiv)was added and the mixture stirred for 15 min. After this time isobutylchloroformate (127 mg, 0.929 mmol, 1.1 equiv) was added. After stirringfor 30 min LC-MS showed remaining starting material. The procedure wasrepeated with an additional 0.55 equiv of the amine and chloroformate.This consumed all of the starting material. The reaction mixture wasquickly filtered through a pad of celite into a solution of NaBH₄ (128mmol, 3.4 mmol, 4.0 equiv) in water (4 mL). The filter cake was washedwith an additional dry THF (5 mL). LC-MS analysis showed formation ofthe desired alcohol. The solvent was removed and the residue partitionedbetween EtOAc and brine. The layers were separated and the aqueous layerextracted with additional EtOAc. The combined organic layers were driedover Na₂SO₄. The solvent was removed to yield 2-(trimethylsilyl)ethyl3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate (240 mg, 90%)as an orange oil. ¹H and ¹⁹F NMR were consistent with the desiredproduct.

Step 11.2-(2-(Trimethylsilyl)ethoxycarbonylamino)-1-(3,3-difluorocyclobutyl)-3-(N-(t-butoxycarbonyl)-N-methylamino)-propane

2-(Trimethylsilyl)ethyl3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate (240 mg, 0.776mmol) was dissolved in CH₂Cl₂ (4 mL) and the solution was cooled to 0°C. DIEA (301 mg, 2.32 mmol, 3.0 equiv) was added followed by MsCl (133mg, 1.16 mmol, 1.5 equiv) and the mixture was stirred for 30 min at 0°C. LC-MS analysis showed consumption of the alcohol and formation of thedesired mesylate. The reaction was quenched by addition of aq citricacid (10% by weight). The layers were separated and the aqueous phasewas extracted with additional CH₂Cl₂. The combined organic layers weredried over Na₂SO₄, filtered and solvent was removed. The residue wastaken up in methylamine solution (30 wt % in ethanol, 10 mL). Methanolwas added dropwise to aid dissolution. The mixture was divided intothree 4 mL portions. Each portion was separately heated to 150° C. for 7min in a CEM microwave reactor. The four reaction mixtures were combinedand volatile materials were removed. The residue was dissolved inacetonitrile (7 mL) and 1.0 M aq NaOH (2.0 mL) was added, followed byBoc₂O (186 mg, 0.854 mmol, 1.1 equiv). After 1 h starting amine wasstill observed by LC-MS and additional Boc₂O (1.1 equiv) was added.After 1 h all the amine was converted into the Boc derivative. Thesolvent was removed in vacuo and the residue was taken up in EtOAc andwater. The layers were separated and the organic layer was washed withsat'd aq NaHCO₃, brine and evaporated. The diamine was purified by flashchromatography on 12 g of silica, eluting with a 0 to 50% EtOAc inhexanes gradient. The fractions which stained with ninhydrin werecombined and evaporated to yield2-(2-(trimethylsilyl)ethoxycarbonylamino)-1-(3,3-difluorocyclobutyl)-3-(N-(t-butoxycarbonyl)-N-methylamino)-propane(56 mg, 15%) of the diprotected amine. ¹H and ¹⁹F NMR were consistentwith the desired product.

Example 101(1R,2R)-2-amino-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-propan-1-ol

Step 1. (2S)-3-acetoxy-2-(t-butoxycarbonylamino)-N-methylpropanamide

A three-neck, 3 L flask was dried under N₂, cooled, equipped with anoverhead stirrer and charged with a solution of DCC (20.6 g, 0.1 mol) inCH₂Cl₂ (0.65 L). This was cooled to 0° C. and solid Boc-Ser-OH (20.06 g,0.1 mole) was added in one portion. This mixture was stirred for 5 min.Methylamine (33% w/w solution in EtOH, 12.5 mL, 0.1 mol) was addeddropwise over 10 min maintaining the internal temperature below 8° C.The reaction was stirred for an additional 10 min, the cooling bath wasemptied, and the reaction was stirred for 12 h; LC-MS (3 min) t_(R)=0.75min, m/z 241 (M+Na) indicated full conversion. DMAP (1.0 g, 0.008 mol)then acetic anhydride (105.0 mL, 1.1 mol) were added using an externalwater bath to moderate the exotherm (internal temp <30° C.). Thereaction was stirred for 60 min. Celite (25 g) and Et₂O (1 L) wereadded, the mixture was cooled to 0° C. and filtered through a pad ofCelite and then a pad of SiO₂. The filtrate was evaporated under reducedpressure. The resulting oil was chased with tolulene (3×100 mL) andseparated by chromatography on a SiO₂ column to yield(2S)-3-acetoxy-2-(t-butoxycarbonylamino)-N-methylpropanamide (20.4 g,78%). LC-MS (3 min) t_(R)=0.75 min, m/z, 283 (M+Na).

Step 2.(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-((2-trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol

A solution of BH₃ in THF (1.0 M, 0.25 L, 250 mmol) was added dropwiseover 15 min to a solution of(2S)-3-acetoxy-2-(t-butoxycarbonylamino)-N-methylpropanamide (20.4 g,78.5 mmol) in THF (0.5 L) at 0° C. The cooling bath was removed and thereaction was permitted to come to rt overnight. The reaction mixture wascooled to 0° C. (internal temp) and H₂O (20 mL, 1.11 mol) was addeddropwise over 30 min (internal temp maintained below 5° C.). The pH wasadjusted (pH<1) with a slight excess of 5 N aq HCl and the mixture wasstirred for 30 min at 0° C. A solution of K₂CO₃ (57.96 g, 420 mmol) inH₂O (210 mL) and Teoc-OSu (21 g, 81 mmol) were added. The reactionmixture was permitted to warm to rt and stirred for 2 h. The solvent wasstripped and the residue was taken up in EtOAc (0.5 L), washed with 1Naq HCl and brine, dried over Na₂SO₄, decanted, stripped and purified ona SiO₂ column to give(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-((2-trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol(11.54 g) as a white solid. LC-MS (3 min) t_(R)=1.78 min, m/z=371(M+Na).

Step 3.(1R,2R)-2-(t-butoxycarbonylamino)-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-1-ol

A suspension of(2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-((2-trimethylsilyl)-ethoxycarbonyl)amino)propan-1-ol(627.6 mg, 1.8 mmol) and Dess-Martin periodinane (941.4 mg, 2.2 mmol) in1,2-dichloroethane (5 mL) was heated in a CEM microwave reactor at 70°C. for 3 min. Loss of starting material was confirmed by LC-MS andgeneration of aldehyde was confirmed by TLC(R_(f)=0.4, 5:1hexanes/EtOAc, 2,4-DNP: yellow). The mixture was taken up in 100 mLCH₂Cl₂ (100 mL), washed with 1 N aq NaOH, water and brine, dried overNa₂SO₄, decanted, stripped. The residue (772.3 mg) was carried ondirectly without further purification. The crude aldehyde was taken upin THF (5.0 mL), cooled to −20° C., and cyclopentyl magnesium bromide(0.81 M in THF, 5.0 mL) was added with fast dropwise addition. Thereaction was permitted to warm to rt, stirred for 12 h and quenched withsat'd aq NH₄Cl. The mixture was extracted with ether. The ether extractswere washed with sat'd aq NH₄Cl and brine, and dried over Na₂SO₄,decanted, and stripped. Chromatography on a 12-g SiO₂ cartridge afforded(1R,2R)-2-(t-butoxycarbonylamino)-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol(225.9 mg, 30% overall) as a white solid ( ). LC-MS (3 min) t_(R)=2.19,m/z 439 (M+Na).

Step 4.(1R,2R)-2-amino-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol

A solution of TsOH (36.8 mg, 0.194 mg) in 1.0 mL EtOH (1 mL) was addedto(1R,2R)-2-(t-butoxycarbonylamino)-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol(68.2 mg, 0.164 mmol) in 3.0 mL Et₂O (3 mL). The solvent was removedunder reduced pressure at 60° C. and the residue maintained at thistemperature for 1 h. The residue was taken up into CH₂Cl₂ (50 mL),washed with 1 N aq NaOH and brine, and dried over Na₂SO₄. Removal of thesolvent left(1R,2R)-2-amino-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-olwhich was used without purification.

Example 102 tert-Butyl(2R,3S)-2-amino-3-cyclopentyl-3-hydroxypropylmethylcarbamate

Step 1. 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde

Phthalimidoacetaldehyde diethyl acetal (76.40 g, 0.32 mol, Aldrich) wasdissolved in 85% formic acid (300 mL) and stirred for 2 h at rt. AfterTLC analysis indicated full conversion to the aldehyde (Rf=0.34 1:1hexanes/EtOAc, 2,4-DNP: yellow), the solvent was removed and the residuewas dried under vacuum (150 mm Hg) to afford2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (56.34 g, 93%) as a whitesolid. ¹H NMR: 4.57 (s, 2H), 7.76 (m, 2H), 7.77 (m, 2H), 9.66 (s, 1H).

Step 2.(2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal

2-(1,3-Dioxoisoindolin-2-yl)acetaldehyde (2.017 g, 10.7 mmol) wasdissolved in a minimal amount of anhydrous NMP (5.0 mL). Heating wasrequired for full dissolution. The solution was cooled to rt andcyclopentanecarboxaldehyde (4.91 g, 50 mmol) was added. The solution wascooled to 0° C. and solid L-proline (0.4025 g, 3.4 mmol) was added inone portion. The reaction was stirred for 1 h at 0° C. and then theorange mixture was stored in the refrigerator at 6° C. for 36 h. Themixture was taken up in EtOAc (100 mL), washed with sat'd aq NH₄Cl (3×10mL) and brine (3×10 mL), dried over Na₂SO₄, decanted and stripped togive an orange oil (5.4 g). Chromatography isolation of the UV activealdehyde (R_(f)=0.53 1:1 hexanes/EtOAc) gave(2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal(1.33 g, 44%) as a yellow solid. LC-MS (3 min) t_(R)=1.65 min, m/z 287(M+1).

Step 3.2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione

A solution of(2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal(1.339 g, 4.7 mmol) in dry THF (20 mL) was cooled to 0° C. Acetic acid(2.5 mL, 44 mmol), methylamine (33% in EtOH, 2.5 mL, 20 mmol), andNaHB(OAc)₃ (4.4937 g, 21.3 mmol) were added sequentially in singleportions. The ice bath was removed and the mixture was stirred for 2 hat rt. The solvent was stripped and the crude2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dionewas used directly in the next step. LC-MS (3 min) t_(R)=1.07, m/z=303(M+1).

Step 4.2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-yl)isoindoline-1,3-dione

Crude2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione(≦54.7 mmol) was dissolved in THF (20 mL). A solution of K₂CO₃ (8.3 g,60 mmol) in water (20 mL) was added followed by Boc₂O (6.1 g, 27 mmol).The two-phase system was stirred for 1 h at rt. The mixture wasextracted with ether, washed with sat'd aq NaHCO₃ and brine, dried,decanted, and stripped. Chromatography on silica gel gave2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-yl)isoindoline-1,3-dione(1.25 g, 65%) of a highly crystalline solid. LC-MS (3 min) t_(R)=1.8min, m/z=403 (M+1).

Step 5. tert-Butyl(2R,3S)-2-amino-3-cyclopentyl-3-hydroxypropylmethylcarbamate

2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-yl)isoindoline-1,3-dione(0.7961 mg, 2.0 mmol) was dissolved in a minimal volume of EtOH (20 mL)and hydrazine monohydrate (0.5 mL, 10.3 mmol) was added. The solutionwas heated at 55° C. for 45 min and at reflux for 2 h. A white solid(precipitation of the hydrazone) resulted and the reaction was cooled tort. Ether (50 mL) was added and the reaction was filtered through #1Whatman filter paper. The filtrate was stripped and the residue wasstirred in ether (15 mL) for 1 h, filtered, and stripped to givetert-butyl (2R,3S)-2-amino-3-cyclopentyl-3-hydroxypropyl-methylcarbamate(199.7 mg, 36%). LC-MS (3 min) t_(R)=1.10 min, m/z=272 (M+).

Example 103

The following compounds were prepared using procedures analogous tothose described in Example 102:

-   (2R,3R)-1-(N-(t-butoxycarbonyl)-N-methylamino)-3-cycloheptyl-3-hydroxypropyl-2-amine    using cycloheptanecarboxaldehyde in Step 2.-   tert-butyl (2R,3S)-2-amino-3-hydroxy-4-methylpentyl(methyl)carbamate    using isobutyraldehyde in Step 2.

Example 104 tert-Butyl 2-(methylamino)ethylcarbamate

Step 1. tert-butyl 2-(methanesulfonatyl)ethylcarbamate

A solution of N-Boc-2-aminoethanol (5.0 g, 27.6 mmol) in CH₂Cl₂ (100 mL)was cooled to −20° C. (ice/MeOH bath). Triethylamine (4.8 mL, 1.25equiv) was added, followed by MsCl (2.25 mL, 1.05 equiv) dropwise. Somewhite precipitate formed after the addition of MsCl. After 10 min, thereaction mixture was warmed to rt slowly. After stirring 2 h, thereaction mixture was diluted with ether (400 mL), washed with 5% HClsolution (2×50 mL), water (50 mL) and brine (40 mL), and dried overNa₂SO₄. Evaporation afforded crude tert-butyl2-(methanesulfonatyl)ethylcarbamate (7.82 g, quant) which was usedwithout purification.

Step 2. tert-Butyl 2-(methylamino)ethylcarbamate

tert-Butyl 2-(methanesulfonatyl)ethylcarbamate (417 mg, 1.61 mmol) andmethylamine in methanol solution (33%, 3.81 g, 25 equiv) were mixed andheated in a CEM microwave oven for 5 min at 150° C. The reaction mixturewas concentrated to afford crude tert-butyl2-(methylamino)ethylcarbamate (305 mg, quant). LC-MS showed the reactionwas complete and the crude product was used without purification.

Example 105 Benzyl(S)-2-amino-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate

Step 1. (2S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-propionic acid

To a solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloridesalt (41.5 g, 0.2 mol) in 0.5 N aqueous NaOH (840 mL) was added asolution of Boc₂O (48 g, 0.22 mol) in THF (420 mL) and the mixture wasstirred for about 2 h. After removing the organic solvent, the aqueouslayer was extracted with ether (2×200 mL) and the organic layer wasdiscarded. The aqueous layer was treated with 2N aq HCl until pH 5 andextracted with EtOAc (3×200 mL). The combined organic layers were washedwith brine, and dried over Na₂SO₄, then evaporated to give(2S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid as an oilthat was used in the next step without further purification. ¹H NMR(CDCl₃, 400 MH_(Z)) δ 0.90 (m, 2H), 1.18 (m, 2 H), 1.44 (s, 9H), 1.50(m, 2H), 1.68 (m, 6H), 1.82 (m, 1H), 4.30 (brs, 1H), 5.00 (brs, 1 H).

Step 2. tert-Butyl(S)-1-(2,2,2-trifluoroethylcarbamoyl)-2-cyclohexylethylcarbamate

A mixture of (2S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid(2.98 g, 11 mmol), 2,2,2-trifluoroethylamine (1.35 g, 10 mmol), EDC(2.87 g, 15 mmol), HOBt (2.03 g, 15 mmol) and NMM (5.05 g, 50 mmol) in100 mL of CH₂Cl₂ was stirred overnight. The mixture was poured intowater (50 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄, andevaporated to give the residue. The residue was purified by silicachromatography to give tert-butyl(S)-1-(2,2,2-trifluoroethylcarbamoyl)-2-cyclohexylethylcarbamate (2.8 g,80%). ¹H NMR (CDCl₃, 400 MH_(Z)) δ 0.90 (m, 2H), 1.25 (m, 4H), 1.44 (s,9H), 1.68 (m, 7H), 3.89 (m, 1H), 4.16 (brs, 1H), 4.82 (brs, 1H), 6.78(brs, 1H).

Step 3. tert-Butyl(S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate

To a solution of tert-butyl(S)-1-(2,2,2-trifluoroethylcarbamoyl)-2-cyclohexylethyl-carbamate (1.8g, 5.1 mmol) in anhydrous THF (30 mL) was added 2 M BH₃.Me₂S in THF (25mL, 50 mmol) and the mixture was stirred at rt for 3 d. The reaction wasquenched with MeOH (20 mL), the solvent was removed in vacuo and theresidue was purified by silica chromatography to give crude tert-butyl(S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate (1.7g).

Step 3. Benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate

To a solution of tert-butyl(S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate (1.7g, 5 mmol) and Et₃N (2 mL, 15 mmol) in CH₂Cl₂ (20 mL) was added dropwisea solution of CbzCl (1.02 g, 6 mmol) in CH₂Cl₂ (10 mL) at 0° C. Afterstirring for an additional 2 h, water (30 mL) was added. The mixture wasextracted with CH₂Cl₂ (2×20 mL), the organic layers were washed withbrine, dried over MgSO₄, and evaporated. The residue was purified bysilica chromatography to obtain benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclohexyl-propyl-2,2,2-trifluoroethylcarbamate(250 mg, yield 10% for 2 steps) as an oil. ¹H NMR (CDCl₃, 400 MH_(Z)) δ0.90 (m, 2H), 1.25 (m, 4 H), 1.44 (s, 9H), 1.70 (m, 7H), 3.33 (m, 2H),3.85 (m, 3H), 4.45 (brs, 1H), 5.20 (s, 2 H), 7.36 (m, 5H).

Step 4. Benzyl(S)-2-amino-3-cyclohexylpropyl-2,2,2-trifluoroethylcarbamate

A solution of benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclohexyl-propyl-2,2,2-trifluoroethylcarbamate(250 mg) in TFA/CH₂Cl₂ (8 mL, 20% v/v) was stirred for 2 h at 0° C. Thereaction was neutralized with satd aq NaHCO₃ and extracted with CH₂Cl₂(3×30 mL). The combined extracts were washed with brine (30 mL), driedover Na₂SO₄ and evaporated to give benzyl(S)-2-amino-3-cyclohexylpropyl-2,2,2-trifluoroethylcarbamate (205 mg)that was used without further purification.

Example 106 Benzyl (S)-2-amino-3-cyclopentylpropylmethylcarbamate

Step 1. (R)-2-Amino-3-hydroxy-propionic acid methyl ester hydrochloride

To a solution of serine (105 g, 1 mol) in methanol (1200 mL) was addedthionyl chloride (87.6 mL, 142.8 g, 1.2 mol) dropwise at 0° C. Afteraddition, the reaction mixture was heated under reflux for 12 h.Volatiles were evaporated to give (R)-2-amino-3-hydroxy-propionic acidmethyl ester hydrochloride (155 g, 100%) as a solid that was usedwithout further purification. ¹H NMR (CDCl₃, 400 MH_(Z)) δ 3.71 (s, 3H),3.79 (m, 2H), 4.08 (s, 1H), 8.51 (br s, 2H).

Step 2. tert-Butyl (R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate

DIEA (194 g, 1.5 mol) was added to a stirred suspension of(R)-2-amino-3-hydroxy-propionic acid methyl ester hydrochloride (155 g,1 mol) in CH₂Cl₂ (1200 mL). A solution of Boc₂O (218 g, 1 mol) in CH₂Cl₂(800 mL) was added dropwise to the above mixture and the reactionmixture was allowed to stir overnight. The solution was washed with 1Naqueous HCl (600 mL), then with sat'd NaHCO₃ (500 mL) and brine (500mL), dried, filtered, evaporated to give tert-butyl(R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (245 g, 96%) as an oilthat was used without further purification. ¹H NMR (CDCl₃, 400 MH_(Z)) δ1.44 (s, 9H), 2.37 (br s, 1H), 3.77 (s, 3H), 3.91 (dd, J=18, 3.2 Hz,2H), 4.35 (s, 1H), 5.29 (br s, 1H).

Step 3. tert-Butyl(R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate

To a solution of tert-butyl(R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (27.5 g, 0.126 mol) inDMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl(20.9 g, 0.139 mol) and the reaction mixture was stirred for 4 h. Thesolvents were removed in vacuo. EtOAc (300 mL) was added and thesolution was washed with sat'd aq NH₄Cl (2×100 mL), sat'd aq NaHCO₃ (100mL) and brine (100 mL), dried, filtered and evaporated to givetert-butyl(R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate (40 g,yield 95%) as an oil that was used without further purification. ¹H NMR(CDCl3, 400 MH_(Z)): δ=0.02 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 3.73(s, 3H), 3.82 (dd, J=14, 4.4 Hz, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H),4.35 (m, 1H), 5.34 (brs, 1H).

Step 4.(S)-2-(t-butoxycarbonylamino)-3-(t-butyldimethylsilyloxy)propan-1-ol

To a solution of tert-butyl(R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)-ethylcarbamate (40g, 0.12 mol) in MeOH (500 mL) at 0° C. was added NaBH₄ (38 g, 1 mol) inportions. The mixture was stirred for 2 h at rt and then evaporated. Theresidue was partitioned between water (200 mL) and EtOAc (2×200 mL). Theorganic layers were washed with sat'd aq NaHCO₃ and brine, dried overMgSO₄ and evaporated to obtain the alcohol(S)-2-(t-butoxycarbonylamino)-3-(t-butyldimethylsilyloxy)propan-1-ol (36g, 98%). ¹HNMR (CDCl₃, 400 MH_(Z)): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.45(s, 9H), 2.25 (brs, 1H), 3.68 (m, 2H), 3.78 (m, 2H), 5.15 (brs, 1H).

Step 5. (S)-tert-butyl2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate

Ph₃P (19.65 g, 75 mmol) was dissolved in 9:1 THF/CH₃CN (600 mL) andcooled to 0° C., DIAD (14.7 mL, 75 mmol) was added dropwise over 15 min.After stirring for 30 min, a solution of(S)-2-(t-butoxycarbonylamino)-3-(t-butyldimethylsilyloxy)propan-1-ol(15.25 g, 50 mmol) in THF (100 mL) was added dropwise over 15 min, thereaction mixture was allowed to rt and stirred for 24 h. Water (100 mL)was added and volatiles were evaporated. The residue was partitionedbetween water (100 mL) and EtOAc (2×100 mL). The organic layers werewashed with brine, dried over MgSO₄ and evaporated. The residue waspurified by silica chromatography to provide (S)-tert-butyl2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate (7.8 g, 54%) asan oil. ¹H NMR (CDCl₃, 400 MHz): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.45 (s,9H), 2.06 (d, J=3.6 Hz 1H), 2.26 (d, J=6 Hz 1H), 2.55 (m, 1H), 3.64 (dd,J=16.4, 4.8 Hz, 1H), 3.82 (dd, J=16.4, 4.4 Hz, 1H).

Step 6. tert-Butyl(S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate

A 100 mL, three-neck flask was charged with Mg powder (720 mg, 30 mmol),and a solution of cyclopentylbromide (3.73 g, 25 mmol) in THF (25 mL)was added dropwise while the flask was heated with a heat gun. Afterstirring for about 2 h, most of the Mg had been consumed. The Grignardreagent was added to a suspension of CuBr.SMe₂ (307.5 mg, 1.5 mmol) inTHF (80 mL) at −78° C., the cuprate was stirred for 30 min and asolution of (S)-tert-butyl2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate (2.87 g, 10mmol) in ether (30 mL) was added. The mixture was stirred for 2 h,washed with sat'd aq NaHCO₃ (2×20 mL) and brine (30 mL), dried overMgSO₄, and evaporated. The residue was purified by silica chromatographyto obtain tert-butyl(S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate (2.9g, 81%) as an oil. ¹H NMR (CDCl₃, 400 MH_(Z)) δ 0.04 (s, 6H), 0.89 (s,9H), 1.10 (m, 2H), 1.44 (s, 9 H), 1.50 (m, 3H), 1.60 (m, 3H), 1.81 (m,3H), 3.58 (m, 3H), 4.60 (brs, 1H).

Step 7. tert-Butyl (S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate

tert-Butyl(S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate (2.9g, 8.1 mmol) was stirred with 1 M Bu₄NF in THF (24.3 mL) at 0° C. for 1h. Water (30 mL) was added and the mixture was extracted with EtOAc(3×40 mL). The combined organic layers were washed with brine, driedover MgSO₄ and evaporated to give crude tert-butyl(S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate that was used in thenext step without further purification. ¹H NMR (CDCl₃, 400 MH_(Z)) δ1.09 (m, 2H), 1.44 (s, 9 H), 1.50 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H),3.52 (m, 1H), 3.68 (m, 2H), 4.60 (brs, 1H).

Step 8. tert-Butyl(S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate

Crude tert-butyl (S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate fromthe previous step was dissolved in CH₂Cl₂ (30 mL). Et₃N (3.2 mL, 24.3mmol) was added and the mixture was cooled to 0° C. A solution of MsCl(1.1 g, 9.7 mmol) in CH₂Cl₂ (10 mL) added dropwise. After stirring foran additional 2 h, water (30 mL) was added and the mixture was extractedwith CH₂Cl₂ (2×30 mL). The combined organic layers were washed withbrine, dried over MgSO₄, and evaporated to give crude tert-butylcyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate that was used inthe next step without further purification. ¹H NMR (CDCl₃, 400 MH_(Z)) δ1.09 (m, 2H), 1.46 (s, 9 H), 1.50 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H),3.02 (s, 3H), 3.86 (m, 1H), 4.17 (dd, J=10, 4 Hz, 1H), 4.27 (dd, J=10,3.2 Hz, 1H), 4.59 (brs, 1H).

Step 9. tert-Butyl (S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate

A mixture of crude tert-butyl(S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate inethanolic methylamine (30 mL) was heated under reflux overnight. Thesolvent was removed in vacuo and the residue was purified by silicachromatography to obtain tert-butyl(S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 43% for 3steps from) as a solid (900 mg, yield 43% for 3 steps from tert-butyl(S)-3-cyclopentyl-1-(t-butyldimethyl-silyloxy)propan-2-ylcarbamate). ¹HNMR (CDCl3, 400 MH_(Z)) δ 1.10 (m, 2H), 1.44 (s, 9H), 1.49 (m, 3H), 1.60(m, 3H), 1.81 (m, 3H), 2.69 (s, 3H), 2.90 (m, 1H), 3.17 (m, 1H), 3.92(brs, 1H), 5.66 (brs, 1H).

Step 10. Benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate

To a mixture of tert-butyl(S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 3.52mmol) and Et₃N (1.5 mL, 10.6 mmol) in CH₂Cl₂ (10 mL) was added dropwisea solution of CbzCl (720 mg, 4.22 mmol) in CH₂Cl₂ (5 mL) at 0° C. Afterstirring for an additional 2 h, water (30 mL) was added and the mixturewas extracted with CH₂Cl₂ (2×10 mL). The combined organic layers werewashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by silica chromatography to obtain benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550mg, 40%) as an oil. ¹H NMR (CDCl₃, 400 MH_(Z)) δ 1.10 (m, 2H), 1.43 (s,9H), 1.49 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H), 2.96 (s, 3H), 3.15 (m,1H), 3.40 (m, 1H), 3.83 (brs, 1H), 4.57 (brs, 1H), 5.16 (s, 2H), 7.33(m, 5H).

Step 11. Benzyl (S)-2-amino-3-cyclopentylpropylmethylcarbamate

A solution of benzyl(S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550mg) in TFA/CH₂Cl₂ (10 mL, 20% v/v) was stirred for 2 h at 5° C. Themixture was neutralized with sat'd aq NaHCO₃ and extracted with CH₂Cl₂(3×30 mL). The combined organic extracts were washed with brine (30 mL),dried over Na₂SO₄ and evaporated to give benzyl(S)-2-amino-3-cyclopentylpropylmethylcarbamate (420 mg) that was used inthe next step without further purification.

Example 107 Benzyl(S)-2-amino-3-(cis-4-fluorocyclohexyl)propylmethylcarbamate

Step 1. tert-butyl(S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)cyclohexyl)-ethylcarbamate

To a solution of TBSCl (12.7 g, 85 mmol) in dichloromethane (20 mL) wasadded dropwise a mixture of2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)-propionic acidmethyl ester (17 g, 56 mmol) and imidazole (7.68 g, 113 mmol) indichloromethane (200 mL) at 0° C. After stirring at rt for 5 h, thereaction mixture was washed with water and brine. The organic layer wasdried over Na₂SO₄ and concentrated to give tert-butyl(S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)cyclohexyl)ethylcarbamate(21 g, 91%) that was used in the next step without further purification.¹H NMR (CDCl₃, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.45 (s, 9H), 1.51(m, 4H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H) 3.71 (d, 3H), 3.91 (m,1H), 4.34 (m, 1H), 4.86 (m, 1H).

Step 2.(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)propan-1-ol

To a solution of tert-butyl(S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)-cyclohexyl)ethylcarbamate(25 g, 60 mmol) in EtOH (500 mL) at 0° C. was added NaBH₄ (18 g, 480mmol) in portions. The mixture was stirred for 6 h at rt and thenevaporated. The residue was partitioned between water (200 mL) and EtOAc(2×200 mL). The combined organic layers were washed with brine, driedover MgSO₄, and evaporated to give(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)propan-1-ol(23 g, yield 98%). ¹H NMR (CDCl₃, 400 MH_(Z)) δ 0.08 (d, 6H), 0.89 (d,9H), 1.30 (m, 4 H), 1.40 (t, 2H), 1.45 (s, 9H), 1.61 (m, 1H), 1.58 (m,1H), 1.68 (t, 4H), 1.85 (d, 1H) 3.50 (m, 1H), 3.65 (m, 1H), 3.73 (m,1H), 3.91 (s, 1H), 4.53 (s, 1H).

Step 3.(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)-1-methanesulfonyloxypropane

To a solution of(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)-cyclohexyl)propan-1-ol(23 g, 59 mmol) in CH₂Cl₂ (250 mL) was added Et₃N (15 g, 148 mmol). Thereaction mixture was cooled to −20° C. and a solution of MsCl (14.9 g,131 mmol) in CH₂Cl₂ (40 mL) added dropwise. After returning to rt thenstirring for an additional 1 h, at which point TLC showed no startingmaterial, water (100 mL) was added and the mixture was extracted withCH₂Cl₂ (2×150 mL). The combined organic layers were washed with brine,dried over MgSO₄ and evaporated to give crude(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethyl-silyloxy)cyclohexyl)-1-methanesulfonyloxypropane(30 g) that was used in the next step without further purification.

Step 4. tert-Butyl(S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate

A solution of crude(2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)-1-methanesulfonyloxypropane(30 g) in methylamine alcohol solution (300 mL) was heated under refluxovernight. The solvent was removed in vacuo and the residue was purifiedby silica chromatography to obtain tert-butyl(S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamateas a solid (15 g, 63% for 2 steps). ¹H NMR (CDCl₃, 400 MHz) δ 0.08 (d,6H), 0.89 (d, 9H), 1.25 (t, 3H), 1.45 (s, 9H), 1.61 (m, 2H), 1.82 (t,2H), 2.01 (d, 1H), 2.56 (d, 2H), 2.80 (d, 2H), 2.95 (t, 2H), 3.49 (m,1H), 3.61 (m, 1H), 3.90 (s, 1H), 5.35 (d, 1H), 7.15 (m, 1H).

Step 5. tert-Butyl(S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate

To a mixture solution of tert-butyl(S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate(112 g, 209 mmol) and Et₃N (52.8 g, 522 mmol) in CH₂Cl₂ (1200 mL) wasadded dropwise a solution of benzyl chloroformate (39 g, 230 mmol) inCH₂Cl₂ (40 mL) at −20° C. After stirring for an additional 2 h, water(400 mL) was added and the mixture was extracted with CH₂Cl₂ (2×200 mL).The organic layers were washed with brine, dried over MgSO₄, andevaporated. The residue was purified by silica chromatography to affordcrude tert-butyl(S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(90 g) as an oil which was a mixture of two isomers. The isomers wereseparated by preparative HPLC. ¹H NMR (CDCl3, 400 MH_(Z)): δ=0.08 (s,6H), 0.89 (s, 9H), 1.28 (m, 4H), 1.40 (d, 9H), 1.59 (m, 4H), 2.96 (d,3H), 3.05 (d, 1H), 3.15 (d, 1H), 3.45 (t, 3H), 3.90 (s, 1H), 5.12 (d,2H), 7.33 (m, 5H).

Step 6. tert-Butyl(S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate

tert-Butyl(S)-1-(trans-4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(18 g, 34 mmol) was treated with 4 M nBu₄NF/THF (50 mL) at 50° C. for 6h. Water (30 mL) was added and the mixture was extracted with EtOAc(3×100 mL). The combined organic layers were washed with brine, driedover MgSO₄ and evaporated to give crude tert-butyl(S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(9 g, 64%) that was purified by silica chromatography. ¹H NMR (CDCl₃,400 MHz) δ 1.41 (d, 9H), 1.65 (m, 6H), 1.95 (m, 3H), 2.98 (d, 3H), 3.10(m, 1H), 3.52 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).

Step 7. tert-Butyl(S)-1-(cis-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate

A mixture of tert-butyl(S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(3 g, 7 mmol), Et₃N (12 mL, 88 mmol), NEt₃(HF)₃ (4.71 mL, 29 mmol) andperfluorobutanesulfonyl fluoride (5.21 mL, 29 mmol) was stirred in THF(70 mL, 1 mmol/10 mL) at 50° C. until HPLC revealed complete conversion.The reaction mixture was quenched with water and extracted with EtOAc(2×100 mL), dried over MgSO₄ and evaporated. The residue was thenpurified by prep HPLC to give tert-butyl(S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(1.16 g, 40%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.41 (d, 9H),1.68 (m, 6H), 1.96 (m, 3H), 2.98 (d, 3 H), 3.20 (m, 1H), 3.52 (m, 1H),3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).

Step 8. Benzyl(S)-2-amino-3-(cis-4-fluorocyclohexyl)propylmethylcarbamate

A solution of tert-butyl(S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate(550 mg, 1.3 mmol) in TFA/CH₂Cl₂ (20 mL, v/v 20%) was stirred for 1 h atrt, quenched with satd aq NaHCO₃ until no further gas evolution wasvisible and extracted with CH₂Cl₂ (2×50 mL). The combined organic layerswere washed with brine, dried over MgSO₄, filtered and condensed underreduced pressure to obtain benzyl(S)-2-amino-3-(cis-4-fluorocyclohexyl)propylmethylcarbamate (400 mg,yield 95%). ¹H NMR (CDCl₃, 400 MHz) δ 1.42 (m, 4H), 1.64 (m, 4H), 2.98(d, 3H), 3.21 (m, 1H), 3.50 (m, 1H), 3.90 (m, 1 H), 5.13 (d, 2H), 7.33(m, 5H).

Example 108 Benzyl(S)-2-amino-3-(trans-4-fluorocyclohexyl)propylmethylcarbamate

Step 1. Benzyl(S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)propyl-(methyl)carbamate

A mixture of benzyl(S)-2-(t-butoxycarbonylamino)-3-(cis-4-hydroxycyclohexyl)-propyl(methyl)carbamate(1 g, 2.38 mmol), base Et₃N (5 mL, 28 mmol), a fluoride source NEt₃(HF)₃(1.9 mL, 9.52 mmol) and perfluorobutanesulfonyl fluoride (2.1 mL, 9.52mmol) were stirred in THF (24 mL, 1 mmol/10 mL) in a capped vial orflask at 50° C. until LC revealed complete conversion. The reactionmixture was quenched with water and extracted with EtOAc (2×100 mL),dried over MgSO₄, and evaporated. The residue was then purified bypreparative HPLC to give benzyl(S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)propyl-(methyl)carbamate(200 mg, 20%) as a white solid.

Step 2. (2-Amino-3-(4-fluoro-cyclohexyl)-propyl)-methyl-carbamic acidbenzyl ester

A solution of benzyl(S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)-propyl(methyl)carbamate(200 mg, 0.47 mmol) in TFA/CH₂Cl₂ (15 mL, v/v 20%) was stirred for 1 hat rt, then quenched by addition of sat'd aq NaHCO₃ solution until gasevolution ceased. The mixture was extracted with CH₂Cl₂ (2×50 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure to obtain benzyl(S)-2-amino-3-(trans-4-fluorocyclohexyl)propyl(methyl)carbamate (140 mg,yield 93%). ¹HNMR (CDCl₃, 400 MH_(Z)): δ 1.42 (m, 4H), 1.64 (m, 4H),2.98 (d, 3H), 3.21 (m, 1H), 3.50 (m, 1H), 3.90 (m, 1 H), 5.13 (d, 2H),7.33 (m, 5H).

Example 109 (S)-2-(trimethylsilyl)ethyl2-amino-3-(4-(tert-butyldimethylsilyloxy)-cyclohexyl)propyl(methyl)carbamate

Step 1. (S)-tert-butyl1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate

Solid Teoc-OSu (1.35 g, 5.25 mmol) was added to a two-phase solution of(S)-tert-butyl1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate(2.0 g, 5.0 mmol), K₂CO₃ (0.75 g, 9.0 mmol) in H₂O (6 ml) and CH₂Cl₂ (12mL). The mixture was vigorously stirred for 2 h at rt. The product wasextracted with CH₂Cl₂. The combined organic layers were washed withsat'd aq NaHCO₃ and brine, dried over Na₂SO₄ and evaporated. The residuewas purified by column chromatography to provide (S)-tert-butyl1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate(1.9 g, 3.49 mmol, 70% yield). ¹H NMR (400 MHz, CD₃OD): 0.05 (s, 15H),0.87 (s, 9H), 1.40 (s, 9H), 1.69 (s, 3H), 2.96 (m, 3H), 3.40-3.52 (m,1H), 3.81-3.92 (m, 1H), 4.12-4.29 (m, 2H). MS (E/Z): 545 (M+H⁺)

Step 2. (S)-2-(trimethylsilyl)ethyl2-amino-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-propyl(methyl)carbamate

(S)-tert-butyl1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate(1.9 g, 3.49 mmol) was dissolved into a minimal volume of Et₂O (23.4 mL)and added to a solution of TsOH (0.66 g, 3.49 mmol) in absolute EtOH (5mL). This solution was placed on a rotary evaporator and the Et₂O wasremoved at ambient temperature. The flask was then lowed into the waterbath (temperature: 60° C.) and the selective deprotection of the Bocgroup proceeded concurrent with removal of the remainder of solvent. Thereaction was complete after 2 h and gave a pale yellow oil. The residuewas dissolved into EtOAc (30 mL) and washed with 1 M aq NaOH (3×5 mL),brine (4×5 mL). The combined organic layers were dried and concentratedto provide (S)-2-(trimethylsilyl)ethyl2-amino-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propyl(methyl)carbamate(1.15 g, 74%). MS (E/Z): 445 (M+H⁺).

Example 110 tert-Butyl2-amino-3-(1-fluorocyclohexyl)propyl(methyl)carbamate

Step 1. tert-Butyl3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)-propyl(methyl)carbamate

To a solution of tert-butyl3-(1-hydroxycyclohexyl)-2-(4-methylphenylsulfonamido)-propyl(methyl)carbamate(9.23 g, 21 mmol) in dry CH₂Cl₂ (100 mL) at −78° C. was added(dimethylamino)sulfur trifluoride (4.2 g, 32 mmol). The reaction mixturewas poured into water (80 mL) and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica eluted with 10:90 hexanes/EtOAc to afford a light yellowsolid. The crude product was purified further by preparative HPLC togive tert-butyl3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)propyl(methyl)carbamate(1.85 g). ¹H NMR (400 MHz, CDCl₃): 1.24-1.52 (m, 19H), 1.74-1.79 (m,3H), 2.42 (s, 3H), 2.50 (s, 3H), 3.15 (m, 1H), 3.40 (m, 2H), 7.30 (d,2H), 7.72 (d, J=8.4, 2H). MS (E/Z): 443 (M+H⁺).

Step 2. tert-Butyl 2-amino-3-(1-fluorocyclohexyl)propyl(methyl)carbamate

A solution of sodium naphalenide in anhydrous DME was prepared by addinganhydrous DME (20 mL) to a mixture of sodium (0.3 g, 13 mmol) andnaphthalene (2.1 g, 16 mmol) and stirring the resulting mixture at rtfor 2 h. A solution of tert-butyl3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)propyl(methyl)carbamate(200 mg, 0.43 mmol) in anhydrous DME (15 mL) was cooled in dryice-isopropyl alcohol bath. The sodium naphthalenide solution was addeddropwise to the well-stirred tosylamide solution until a light greencolor persisted. The reaction was quenched with water, diluted withEtOAc and washed with 1 N aq HCl. The aqueous phase was basified withK₂CO₃, and extracted with EtOAc (3×20 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive (S)-[2-amino-3-(1-fluoro-cyclohexyl)-propyl]-methyl-carbamic acidtert-butyl ester (50 mg, 45%).

Example 111 (S)-2-(Trimethylsilyl)ethyl2-amino-4-methoxy-4-methylpentyl(methyl)carbamate

Step 1. (S)-Methyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate

To a stirred solution of(S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-oxobutanoic acid (9.0 g,35.7 mmol) in THF (180 mL) at −10° C. was added N-methylmorpholine (3.9mL, 35.7 mmol) followed by ethyl chloroformate (3.91 g, 35.7 mmol).After 10 min, the mixture was transferred slowly to a mixture of NaBH₄(2.7 g, 71.4 mmol) and ice water (900 mL). The resulting solution wasstirred for 1 h, NaHCO₃ (˜20 g) was added, and the organic layer wasseparated. The aqueous layer was extracted with EtOAc (4×200 mL). Thecombined organic layers were washed with 1 N aq HCl (20 mL) and brine(15 mL), dried over Na₂SO₄, and concentrated to give (S)-methyl3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.06 g, 85%) as an oil.MS m/z 234 (M+H⁺).

Step 2. (S)-tert-Butyl4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate

To a solution of (S)-methyl3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.0 g, 30.0 mmol) inacetone (90 mL), there was added 2,2-dimethoxypropane (37 mL, 300 mmol)followed by BF₃.Et₂O (0.11 mL, 0.9 mmol). The resulting solution wasstirred at rt overnight. Solvents were removed under vacuum, and theresidue was redissolved in ether (100 mL), washed with sat'd NaHCO₃ (20mL). Upon concentrating under vacuum, the residue was purified by flashcolumn chromatography to give (S)-tert-butyl4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate (7.51 g,92%). MS m/z 296 (M+Na⁺).

Step 3. (S)-tert-Butyl4-(2-hydroxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate

To a stirred solution of (S)-tert-butyl4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.56 g,5.71 mmol) in toluene (10 mL) at −20° C., was added methylmagnesiumchloride in THF (3 M, 7.61 mL) dropwise to keep the solution temperaturebelow −20° C. After addition, the solution was allowed to warm to rtslowly, and stirred for another 1 h. Sat'd aq NH₄Cl (5 mL) was added,and the organic layer was washed with water (10 mL), and concentratedunder vacuum. The residue was purified by flash column chromatography togive (S)-tert-butyl4-(2-hydroxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (0.93g, 60%) as an oil. ¹H NMR (400 MHz, CDCl₃): 4.18 (m, 1H), 4.00 (m, 2H),3.80 (m, 1H), 1.92 (m, 1H), 1.74 (m, 1 H), 1.44 (ss, 15H), 1.24 (s, 6H);MS m/z 296 (M+Na⁺).

Step 4. (S)-tert-Butyl4-(2-methoxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate

To a stirred solution of (S)-tert-butyl4-(2-hydroxy-2-methylpropyl)-2,2-dimethyl-oxazolidine-3-carboxylate(0.93 g, 3.4 mmol) in anhydrous THF (8 mL), there was added NaH (60 wt %in mineral oil, 0.41 g, 10.2 mmol) followed by iodomethane (1.46 g, 10.2mmol). The resulting mixture was stirred at rt until no startingmaterial remained (˜5 h). The reaction was quenched by slow addition ofwater, the organic layer was separated, and aqueous layer was extractedwith ether (2×5 mL). The combined organic layers were washed with 1 N aqHCl (5 mL), sat'd aq NaHCO₃ (5 mL) and brine (5 mL), dried over Na₂SO₄and concentrated to give crude (S)-tert-butyl4-(2-methoxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.2g, quant.) which was used without purification. MS m/z 310 (M+Na⁺).

Step 5. (S)-tert-Butyl 1-hydroxy-4-methoxy-4-methylpentan-2-ylcarbamate

To a solution of (S)-tert-butyl4-(2-methoxy-2-methylpropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.2g, 3.40 mmol) in MeOH (5 mL) at rt, there was added4-methylbenzenesulfonic acid (0.65 g, 3.40 mmol). The resulting solutionwas stirred until no starting material remained (˜1 h). Solvent wasremoved under vacuum, and the residue was redissolved in acetone (3 mL)and H₂O (1 mL). Excess K₂CO₃ was added to keep the solution basic,followed by (Boc)₂O. The mixture was stirred for 20 min, acetone wasremoved under vacuum, and the aqueous solution was extracted with CH₂Cl₂(4×5 mL). After concentration, the residue was purified by flash columnchromatography to give (S)-tert-butyl1-hydroxy-4-methoxy-4-methylpentan-2-ylcarbamate (0.76 g, 78%, 2 steps).¹H NMR (400 MHz, CDCl₃): 5.38 (br, 1H), 3.78 (m, 1H), 3.66 (m, 1H), 3.56(m, 1H), 3.20 (s, 3H), 1.66 (m, 2H), 1.62 (br, 1H), 1.44 (s, 9 H), 1.20(s, 6H); MS m/z 248 (M+H⁺).

Step 6. (S)-2-(tert-Butoxycarbonylamino)-4-methoxy-4-methylpentylmethane-sulfonate

To a solution of (S)-tert-butyl 1-hydroxy-4-methoxy-4-methylpentan-2-ylcarbamate (0.74 g, 2.99 mmol) in anhydrous CH₂Cl₂ (15 mL) andtriethylamine (1.67 mL, 12.0 mmol) at −20° C., there was addedmethanesulfonyl chloride (0.69 g, 6.0 mmol) dropwise to keep thesolution temperature below −20° C. After addition, the solution waswarmed to rt slowly, and stirred for another 2 h. Water (5 mL) wasadded, and the organic layer was separated. The aqueous layer wasextracted with CH₂Cl₂ (2×5 mL), and the combined organic layers werewashed with 1 N aq HCl (5 mL), water (5 mL) and brine (5 mL), and driedover Na₂SO₄. Solvent was removed under vacuum to give(S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-methylpentylmethane-sulfonate (1.08 g, quant.), which was used for the next stepwithout purification. MS m/z 348 (M+Na⁺).

Step 7. (S)-tert-Butyl4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate

To a solution of(S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-methylpentylmethane-sulfonate (1.08 g, 2.99 mmol) in MeOH was added methylamine inmethanol (33 wt %, 4.0 mL). The resulting solution was heated in CEMmicrowave reactor at 120° C. for 5 min. Reaction completion wasconfirmed by LC-MS. Solvent was removed under vacuum to give a crude(S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate,which was used for the next step without purification. MS m/z 261(M+H⁺).

Step 8. (S)-tert-butyl4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)pentan-2-ylcarbamate

To a solution of the above (S)-tert-butyl4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate (˜2.99 mmol) inacetone (9 mL) and water (3 mL), there was added K₂CO₃ (1.24 g, 9.0mmol), followed by Teoc-OSu (0.85 g, 3.29 mmol). The resulting mixturewas stirred at rt until no starting material remained (˜1 h). Acetonewas removed under vacuum, and the aqueous residue was extracted withCH₂Cl₂ (4×5 mL). The combined organic layers were concentrated, andcrude residue was purified with flash column chromatography to give(S)-tert-butyl4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate(0.18 g, 15%, 3 steps) as a clear oil. ¹H NMR (400 MHz, CDCl₃): 4.82,4.92 (br, 1H), 4.16 (m, 2H), 3.88 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H),3.16 (s, 3H), 2.88, 2.90 (s, 3 H), 1.44 (s, 9H), 1.18, 1.20 (s, 6H),0.98 (m, 2H), 0.02 (s, 9H); MS m/z 405 (M+H⁺).

Step 9. (S)-2-(Trimethylsilyl)ethyl2-amino-4-methoxy-4-methylpentyl(methyl)-carbamate

To a solution of (S)-tert-butyl4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)pentan-2-ylcarbamate(0.17 g, 0.42 mmol) in ether (2.0 mL) was added a solution ofp-toluenesulfonic acid (80.7 mg, 0.43 mmol) in ethanol (1.0 mL).Transfer of the p-toluenesulfonic acid was completed with the aid ofadditional ether (1.0 mL). The solution was placed on a rotaryevaporator and the ether was removed at rt. Then, with continuingevacuation, the bath temperature was raised to 60-65° C. for 20 min,during which gas evolution was evident. After cooling down to rt, thesolid residue (S)-2-(trimethylsilyl)ethyl2-amino-4-methoxy-4-methylpentyl(methyl)-carbamate was used withoutfurther purification as a p-toluenesulfonic acid salt. MS m/z 291(M+H⁺).

Example 112(3R)-3-((S)-1-(2-(2-Ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Step 1.(2R)-2-(p-nitrophenoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxy-carbonyl)amino)-1-(trimethylsilyloxy)propane

(2-(Trimethylsilyl)ethyl) (R)-2-amino-3-trimethylsilyhydroxypropylmethylcarbamate was dissolved in dry CH₂Cl₂ (4 mL) and pyridine (0.35 mL) wasadded, followed by 4-nitrophenyl chloroformate (0.35 g, 2.11 mmol) atrt. The resulting solution was stirred until no starting materialremained (˜1 h), and the solution of(2R)-2-(p-nitrophenoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propanewas used directly without isolation. MS m/z 486 (M+H⁺).

Step 2.(3R)-3-((S)-1-(2-(2-Ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

To a solution of(S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(19.9 mg, 0.05 mmol) in CH₂Cl₂ (0.5 mL) was added the solution of(2R)-2-(p-nitrophenoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propane(0.05 mmol), followed by DIEA (26 μL, 0.15 mmol). The resulting yellowsolution was stirred at rt for 30 min. CH₂Cl₂ was removed in vacuo andthe residue was redissolved in acetonitrile, and purified by prep HPLCto give(3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(10.0 mg, 30%). MS m/z 672 (M+H⁺).

Step 3.(3R)-3-((S)-1-(2-(2-Ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

To a solution of(3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(10.0 mg, 0.01 mmol) in acetonitrile (1.0 mL) was added excesstetraethylammonium fluoride. The resulting solution was heated at 50° C.for 2 h, and concentrated under vacuum. The residue was purified by prepHPLC to give(3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (2 mg) as its TFA salt. ¹H NMR (400MHz, CD₃OD) 7.62 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H),6.56 (d, 1H), 4.40 (d, 1H), 4.00 (m, 1H), 3.92 (d, 1H), 3.60 (m, 1H),3.54 (m, 1H), 3.26 (t, 2H), 3.24 (s, 3H), 3.22 (m, 1H), 3.04 (m, 1H),2.82 (m, 1H), 2.64 (s, 3H), 2.62 (q, 2H), 2.42 (m, 2H), 1.94 (m, 1H),1.24-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 528 (M+H⁺).

Example 113(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-245A)

Step 1.(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclo-hexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

To a solution of (2-(trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate (18.3 mg, 0.055mmol) in CH₂Cl₂ (2 mL) were added Et₃N (0.2 mL) and Me₃SiCl (12 mg, 14μL, 0.11 mmol). The resulting solution was stirred for 1 h andevaporated under vacuum. The residue was dissolved in CH₂Cl₂ (2 mL),then pyridine (0.05 mL) was added, followed by 4-nitrophenylchloroformate (13.5 mg, 0.66 mmol). The mixture was stirred for 30 minand (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride (19 mg, 0.055 mmol) was added. The mixture was stirred for10 min and evaporated. The residue was purified by prep HPLC to give(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilypethoxy-carbonyl)amino)propan-2-yl)piperidine-1-carboxamide(20 mg, 54%). MS m/z 668 (M+H⁺).

Step 2.(3R)-3-((S)-1-(3-Chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

To a solution of(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(20 mg, 0.03 mmol) in anhydrous THF (1 mL) was added Et₄NF (3 mg). Thesolution was stirred at 45° C. for 2 h and evaporated under reducedpressure. The residue was purified by prep HPLC to give(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(13.2 mg, 71%) as its TFA salt. ¹H NMR (400 MHz, CD₃OD): 7.43 (t, 1H),7.32-7.21 (m, 3H), 4.42 and 4.29 (two isomers on 1 to 1 ratio, d, 1H),4.15 (m, 1H), 3.95 and 3.83 (two isomers on 1 to 1 ratio, d, 1H), 3.34(m, 1H), 3.27 (s, 3H), 3.14 (m, 1H), 2.99 (m, 1H), 2.80 (s, 3H),2.64-2.38 (m, 3H), 1.94 (t, 2H), 1.76 (m, 2H), 1.68-1.18 (m, 20H), 0.98(m, 1H); MS m/z 524 (M+H⁺).

Example 114(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-187A)

Step 1.(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

To a solution of 2-(trimethylsilyl)ethyl3-(1-hydroxycyclohexyl)-2-amino-propylmethylcarbamate (18.3 mg, 0.055mmol) in CH₂Cl₂ (2 mL) was added Et₃N (0.2 mL) and TMSCl (12 mg, 14 μL,0.11 mmol). The resulting solution was stirred for 1 h and evaporatedunder vacuum. The residue was dissolved in CH₂Cl₂ (2 mL) and pyridine(0.05 mL) was added, followed by 4-nitrophenyl chloroformate (13.5 mg,0.66 mmol). The solution was stirred for 30 min and(S)-1-(3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride (18 mg, 0.055 mmol). The resulting mixture was stirred for10 min and evaporated. The residue was purified by prep HPLC to give(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(17.8 mg, 50%). MS m/z 652 (M+H⁺).

Step 2.(3R)-3-((S)-1-(3-Fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

To a solution of(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-piperidine-1-carboxamide(17.8 mg, mmol) in anhydrous THF (1 mL) was added Et₄NF (3 mg). Thesolution was stirred at 45° C. for 2 h and evaporated under reducedpressure. The residue was purified by prep HPLC to give(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(9.5 mg, 58%) as a TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.32 (q, 1H),7.16 (m, 1H), 7.14 (m, 1H), 6.94 (m, 1H), 4.42 and 4.28 (two isomers ina 3:2 ratio, d, 1H), 4.15 (m, 1H), 3.95 and 3.84 (two isomers on 3 to 2ratio, d, 1H), 3.32 (m, 1H), 3.26 (s, 3H), 3.14 (dd, 1H), 2.95 (m, 1H),2.70 (s, 3H), 2.60-2.39 (m 3H), 1.94 (t, 2H), 1.79-1.22 (m, 20H), 1.00(m, 1H); MS m/z 508 (M+H⁺).

Example 115(3R)-3-((S)-1-(3-Fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide(I-188A)

Step 1.(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide

To a solution of1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol(12 mg, 0.036 mmol) in CH₂Cl₂ (1.5 mL) was added Et₃N (0.1 mL) and TMSCl(7.8 mg, 9 μL, 0.073 mmol). The resulting solution was stirred for 1 hand evaporated under vacuum. The residue was dissolved in CH₂Cl₂ (1.5mL) and pyridine (0.03 mL) was added, followed by 4-nitrophenylchloroformate (9 mg, 0.043 mmol). The solution was stirred for 30 minand (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride (14 mg, 0.043 mmol) was added. The resulting mixture wasstirred for 10 min and evaporated. The residue was purified by prep HPLCto give(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxy-carbonyl)amino)propyl)piperidine-1-carboxamide(12.5 mg, 53%). MS m/z 652 (M+H⁺).

Step 2.(3R)-3-((S)-1-(3-Fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide

To a solution of(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide(9.7 mg, 0.015 mmol) in anhydrous THF (1 mL) was added Et₄NF (3 mg). Thesolution was stirred at 45° C. for 2 h and evaporated under reducedpressure. The residue was purified by prep HPLC to give(3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide(4.5 mg, 50%) as its TFA salt. ¹H NMR (400 MHz, CD₃OD): 7.32 (t, 1H),7.16 (d, 1H), 7.14 (d, 1H), 6.94 (td, 1H), 4.36 (t, 1H), 3.88 (t, 1H),3.53 (m, 1H), 3.40 (m, 1H), 3.26 (s, 3H), 2.61 (s, 3H), 2.48 (m, 1H),2.47 (m, 1H), 1.94 (t, 2H), 1.90 (td, 1H), 1.76 (tt, 1H), 1.69-1.22 (m,18H), 0.99 (m, 1H); MS m/z 524 (M+H⁺).

Example 116(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide(I-246A)

Step 1.(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxy-cyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide

To a solution of1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol(21 mg, 0.064 mmol) in CH₂Cl₂ (2 mL) was added Et₃N (0.2 mL) and TMSCl(13.9 mg, 164, 0.13 mmol). The resulting solution was stirred for 1 hand evaporated under vacuum The residue was dissolved in CH₂Cl₂ (2 mL)and pyridine (0.05 mL) was added, followed by 4-nitrophenylchloroformate (15 mg, 0.077 mmol). The solution was stirred for 30 minand (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olhydrochloride (27 mg, 0.077 mmol) was added. The resulting mixture wasstirred for 10 min and evaporated. The residue was purified bypreparative HPLC to give(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide(22 mg, 51%). MS m/z 668 (M+H⁺).

Step 2.(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide

To a solution of(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide(10.7 mg, 0.016 mmol) in anhydrous THF (1 mL) was added Et4NF (3 mg).The solution was stirred at 45° C. for 2 h and evaporated under reducedpressure. The residue was purified by preparative HPLC to give(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(6.3 mg, 64%) as its TFA salt. ¹H NMR (400 MHz, CD₃OD): 7.43 (d, 1H),7.33-7.21 (m, 3), 4.37 (t, 1H), 3.88 (t, 1H), 3.54 (m, 1H), 3.40 (m,1H), 3.33 (m, 1H), 3.27 (s, 3H), 2.60 (q, 1H), 2.46 (m, 1H), 1.94 (t,2H), 1.86 (dt, 1H), 1.76 (tt, 1H), 1.68-1.21 (m 18H), 0.99 (m, 1H); MSm/z 524 (M+H⁺).

Example 117

The following compounds were prepared using procedures analogous tothose described in Examples 113-116:

Cpd. No. Name I-186A(3R)-N-((2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-186B(3R)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-202A(3R)-N-((1R,2R)-3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamideI-202B(3R)-N-((1S,2R)-3-amino-1-cyclohexyl-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamideI-203A (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1R,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-203B(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-244A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1R,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-244B(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-353A(R)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-360A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-371A(R)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-392A(3R)-3-((S)-4-acetamido-1-(2,3-difluorophenyl)-1-hydroxybutyl)-N-((2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-395A(R)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-405A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-427A(R)-N-((2R,3S)-3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide I-428A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-447A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1R,2R)-1-cycloheptyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-452A(R)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-457A(R)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide I-463A(R)-3-((S)-1-(3-fluoro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((2R,3S)-3-hydroxy-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-466A(R)-N-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-phenoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-489A(3R)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide I-497A(3R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Example 118(3R)—N—((S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(I-331A)

Step 1. Benzyl(S)-2-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate

A solution of benzyl(S)-2-amino-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate (74.4 mg,0.2 mmol) and CDI (32.4 mg, 0.2 mmol) in CH₂Cl₂ (5 mL) cooled to 0-5° C.and DIEA (0.5 mL) was added. After stirring for 30 min, a solution of1-(3-chloro-phenyl)-5-methoxy-1-piperidin-3-yl-pentan-1-ol (62.2 mg, 0.2mmol) in CH₂Cl₂ (3 mL) was added dropwise. The mixture was allowed towarm to rt and stirred overnight. The mixture was washed with water (10mL). The aqueous layer was extracted with CH₂Cl₂ (2×15 mL) and thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified by prep HPLC to givebenzyl(S)-2-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate(85.2 mg, 60%).

Step 2.(3R)—N—((S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

To a solution of benzyl(S)-2-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl2,2,2-trifluoroethylcarbamate(85.2 mg, 0.12 mmol) in EtOAc (10 mL) was added PdCl₂ (25 mg) and themixture was stirred under a hydrogen balloon at rt for 3-5 hrs. Afterfiltration, the filtrate was evaporated to give a residue, which waspurified by prep HPLC to give(3R)—N—((S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(25.2 mg, yield 36.5%). ¹H NMR (CDCl₃, 400 MHz) δ 0.90-1.5 (m, 10H),1.54 (m, 2H), 1.69 (m, 8H), 1.82 (m, 1H), 2.96 (m, 1H), 2.33 (m, 1H),2.61 (t, 1H), 3.25 (m, 2H), 3.28 (s, 3H), 3.33 (m, 2H), 3.68 (m, 2H),3.94 (m, 1H), 4.18 (m, 2H), 5.56 (brs, 1H), 7.16 (m, 1H), 7.25 (m, 2H),7.33 (s, 1H).

Example 119

The following compounds were prepared using procedures analogous tothose described in Example 118:

Cpd. No. Name I-156A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-165A(3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-197A(3R)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide I-206A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-206B(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-212A(3R)-3-((R)-(3-methoxypropoxy)(2,3-dichlorophenyl)methyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-239A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-ethoxy-1-hydroxypentyl)piperidine-1-carboxamide I-240B(3R)-N-((S)-3-cyclopropyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxamide I-252A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-253A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-257A(3R)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamideI-265A(3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-266A(3R)-3-((R)-(3-ethoxypropoxy)(2,3-dichlorophenyl)methyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-286A(3R)-3-((S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-295A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(trans-4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-295B(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-139A(3R)-3-((S)-1-hydroxy-5-methoxy-1-(quinolin-8-yl)pentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-199A(3R)-3-((S)-1-(2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-242A(3R)-3-((S)-1-(2-(3-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-243A(3R)-3-((S)-1-(2-(4-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-259A(3R)-3-((S)-1-(3-fluoro-2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-260A(3R)-3-((S)-1-(2-(2-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-261A(3R)-3-((S)-1-(2-(3-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-262A(3R)-3-((S)-1-(2-(4-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-296B(3R)-3-((R)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-296A(3R)-3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-296A(3R)-3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-297A(3R)-3-((S)-1-(2-(4-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-298A(3R)-3-((S)-1-(2-(3-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-359A(R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-368A (R)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-370A(R)-N-((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-370B(R)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-370C(R)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((R)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-399A(R)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-402A(R)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-402B(R)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-403A(R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-403B(R)-3-((R)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-410A(R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1- carboxamideI-432A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-432B(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-435A(R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-435B(R)-3-((R)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-436A(R)-N-((S)-1-(cis-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,5-trifluorophenyl)pentyl)piperidine-1-carboxamide I-467A(R)-3-((S)-1-(3′-chloro-6-fluorobiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-421A(3R)-N-((2S,3S)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-474A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide I-482A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-483A(R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-485A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide I-485B(3R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S,3R)-1-cyclohexyl-3-(methylamino)butan-2-yl)piperidine-1-carboxamide

Example 120(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-429A)

Step 1. 2-(Trimethylsilyl)ethyl(S)-3-(4-((tert-butyldimethylsilyl)methyl)cyclohexyl)-2-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-propyl(methyl)carbamate

To a solution of (S)-2-(trimethylsilyl)ethyl2-amino-3-(4-(tert-butyldimethylsilyloxy)-cyclohexyl)propyl(methyl)carbamate(249 mg, 0.561 mmol) and DIEA (241 mg, 1.87 mmol) in dry CH₂Cl₂ (3.5 mL)was added CDI (91 mg, 0.561 mmol) at 0° C. After addition, the reactionmixture was stirred for 1 h at 0° C. and added to a solution of(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(123 mg, 0.374 mmol) in CH₂Cl₂ (3.5 mL). The reaction mixture wasallowed to warm to rt and stirred overnight. After the reaction wascompleted by analysis of HPLC, the reaction solution was washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuo.The product was purified by preparative TLC to afford2-(trimethylsilyl)ethyl(S)-3-(4-((tert-butyldimethylsilyl)methyl)cyclohexyl)-2-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-propyl(methyl)carbamate(79 mg, 0.0991 mmol, 31%). MS (E/Z): 800 (M+H⁺).

Step 2.(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

A solution of 2-(trimethylsilyl)ethyl(S)-3-(4-((tert-butyldimethylsilyl)methyl)cyclohexyl)-2-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)propyl(methyl)carbamate(79 mg, 0.0991 mmol) and Et₄NF (36.9 mg, 0.248 mmol) in dry CH₃CN (8 mL)was heated under reflux for 2 h. After the reaction was completed byanalysis of HPLC, the mixture was concentrated in vacuo. The product waspurified by preparative HPLC to give two isomeric compounds:(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(trans-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(16 mg, 0.0295 mmol) ¹H NMR (400 MHz, CD₃OD): 2.14 (m, 1H), 2.71 (s,3H), 3.25 (s, 3H), 3.44-3.49 (m, 1H), 3.94-3.98 (m, 1H), 4.12 (m, 1H),4.33-4.37 (m, 1H), 7.16-7.11 (t, 1H), 7.33-7.39 (m, 1H), 7.50-7.55 (m,1H). MS (E/Z): 542 (M+H⁺) and(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(cis-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(10 mg, 0.0185 mmol) ¹H NMR (400 MHz, CD₃OD): 2.14 (m, 1H), 2.71 (s,3H), 3.25 (s, 3H), 3.94-4.02 (m, 1H), 4.12 (m, 1H), 4.33-4.37 (m, 1H),7.16-7.11 (t, 1H), 7.34-7.39 (m, 1H), 7.50-7.54 (m, 1H). MS (E/Z): 542(M÷H⁺).

Example 121

The following compounds were prepared using procedures analogous tothose described in Example 120:

Cpd. No. Name I-119A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(pyridin-2-yl)pentyl)piperidine-1-carboxamide I-125A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(1-methyl-1H-imidazol-2-yl)pentyl)piperidine-1-carboxamideI-126A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiophen-2-yl)pentyl)piperidine-1-carboxamide I-127A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(thiophen-3-yl)pentyl)piperidine-1-carboxamide I-157A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(5-methylthiazol-2-yl)pentyl)piperidine-1-carboxamide I-176A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3,5-dimethylphenyl)pentyl)piperidine-1-carboxamide I-182A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-183A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-5-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-184A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(5-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-185A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-192A(3R)-3-((S)-1-(2-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-196A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-207A (3R)-3-((S)-1-(5-chloro-1-methyl-1H-imidazol-2-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-211A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-1-hydroxy-1-(1H-indazol-7-yl)-5-methoxypentyl)piperidine-1-carboxamide I-219A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-226A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-(methylthio)phenyl)pentyl)piperidine-1-carboxamide I-230A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-fluoro-6-methoxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-237A(3R)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1-carboxamide I-238A(3R)-3-((R)-(3-ethoxypropoxy)(m-tolyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1- carboxamideI-240A(3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4-fluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-248A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(quinolin-8-yl)pentyl)piperidine-1-carboxamide I-250A(3R)-3-((S)-1-(3-chloro-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-255A(3R)-3-((R)-(3-ethoxypropoxy)(3-fluorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1- carboxamideI-264A(3R)-3-((R)-(3-methoxypropoxy)(2,3-dichlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-279A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-280A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(1-(methylamino)-3-(4-methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide I-281A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2-(trifluoromethyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-282A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)piperidine-1-carboxamide I-283A(3R)-3-((S)-1-(2-fluoro-3-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-284A(3R)-3-((S)-1-(2,3-dichlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-285A(3R)-3-((R)-(3-ethoxypropoxy)(2,3-dichlorophenyl)methyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-302A(3R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-308A(3R)-3-((S)-1-(2,3-dichlorophenyl)-5-ethoxy-1-hydroxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-309A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-(trifluoromethoxy)phenyl)pentyl)piperidine-1- carboxamideI-310A(3R)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2-(trifluoromethoxy)phenyl)pentyl)piperidine-1- carboxamideI-317A(3R)-3-((S)-5-ethoxy-1-(2,3-difluorophenyl)-1-hydroxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-320A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-321A(3R)-3-((R)-(3-ethoxypropoxy)(3-chloro-2-fluorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-323A(3R)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3,5-trifluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-324A(3R)-3-((R)-(3-ethoxypropoxy)(2,3,5-trifluorophenyl)methyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-333A(3R)-3-((S)-5-ethoxy-1-(2,3,5-trifluorophenyl)-1-hydroxypentyl)-N-((S)-3-(4,4-difluorocyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-209A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxyethyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-341A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxypropyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-343A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-345A3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide I-346A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-347A(R)-3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-352A(R)-N-((2S,3S)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-358A(R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamideI-362A(R)-3-((S)-4-acetamido-1-(2-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-363A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-363B(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((R)-1-(3-fluoro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-364A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-4-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-364B(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((R)-1-(3-fluoro-4-methylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-366A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(3-fluoro-2-hydroxyphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-372A(R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclopentyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-375A(R)-3-((S)-4-acetamido-1-(3,5-dimethylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-376A(R)-3-((R)-1-cyclohexyl-1-hydroxy-5-methoxypentyl)-N-((S)-1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1- carboxamideI-382A(R)-3-((S)-4-acetamido-1-(3-fluoro-5-methylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-383A(R)-3-((S)-4-acetamido-1-(2-fluoro-5-methylphenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-385A (3R)-3-(1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4-methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-386A(R)-3-((S)-1-(3-chloro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-386B(R)-3-((R)-1-(3-chloro-2-methylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-389A(R)-3-((S)-4-acetamido-1-(3,5-difluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-391A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-391A(R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-393A(R)-3-((S)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-393B(R)-3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-396A(R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-396B(R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-398A(R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-400A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(2,3,4-trifluorophenyl)pentyl)piperidine-1-carboxamide I-401A(R)-N-((S)-1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-417A (3R)-3-(1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-4,4-dimethyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-423A(R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-424A(R)-3-((S)-4-acetamido-1-(3-chloro-5-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-425A(R)-3-((S)-4-acetamido-1-(2-chloro-3-fluorophenyl)-1-hydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-429B(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-433A(R)-3-((S)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-433B(R)-3-((R)-1-(3-chloro-2,4-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-476B(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-476B(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-476C(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-495A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-507A(3S)-3-((R)-1-(3-chlorophenyl)-2-(2-methoxyethoxy)ethyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-531A(3R)-3-((R)-(3-chlorophenyl)(2-propionamidoethoxy)methyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-536A(3R)-N-((2S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((R)-(2,3-difluorophenyl)(2-propionamidoethoxy)methyl)piperidine-1-carboxamideI-537A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyacetamido)ethyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1- carboxamideI-541A(3R)-N-((2S,3S)-3-amino-1-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-545A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-545B(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-546A(3R)-3-((S)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamideI-546B(3R)-3-((R)-4-acetamido-1-(3-chloro-2-fluorophenyl)-1-hydroxybutyl)-N-((2S,3R)-3-amino-1-cyclohexylbutan-2-yl)piperidine-1-carboxamideI-547A(3R)-3-((R)-(3-chloro-2-fluorophenyl)(2-propionamidoethoxy)methyl)-N-((2S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-548A(3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-556A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(cis-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-556B(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(trans-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

The following compounds were prepared using procedures analogous tothose described in Example 120 Step 1 followed by acid catalyzed removalof a Boc protecting group following the conditions described in Example126 Step 2:

Cpd. No. Name I-131A(3R)-3-((S)-1-(2-(3-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-132A(3R)-3-((S)-1-(2-(4-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-133A(3R)-3-((S)-1-(2-(2-methylphenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-140A(3R)-3-((S)-1-(2-(2-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-141A(3R)-3-((S)-1-(3-fluoro-2-phenylphenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-142A(3R)-3-((S)-1-(2-(3-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-143A(3R)-3-((S)-1-(2-(4-fluorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-177A(3R)-3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-178A(3R)-3-((S)-1-(2-(4-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-351A(R)-3-((S)-1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-434A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-367A(R)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-397A(R)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)-3-((S)-1-(2,5-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-428A(R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-430A(R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-456A(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-484A(3R)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-((1r,4S)-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-484B(3R)-3-((R)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-((1r,4S)-4-methoxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-490A(3R)-3-((S)-1-(2-chloro-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Example 122(3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(I-172A)

Step 1. Benzyl(S)-2-((R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclopentylpropylmethylcarbamate

To a solution of (2-amino-3-cyclopentyl-propyl)-methyl-carbamic acidbenzyl ester (87 mg, 0.3 mmol) and CDI (48.6 mg, 0.3 mmol) in CH₂Cl₂ (5mL) cooled to 0-5° C. was added DIEA (0.5 mL). After stirring for 30minutes, a solution of(S)-1-(benzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(95.1 mg, 0.3 mmol) in CH₂Cl₂ (3 mL) was added dropwise. The reactionmixture was allowed to warm to rt and stirred overnight. The mixture waswashed with water (10 mL). The aqueous layer was extracted with CH₂Cl₂(2×15 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered and evaporated. The residue was purified by prepHPLC to give benzyl(S)-2-((R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclopentylpropylmethylcarbamate(98.5 mg, 51.9%).

Step 2.(3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

To a solution of benzyl(S)-2-((R)-3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclopentylpropylmethylcarbamate(98.5 mg, 0.156 mmol) in EtOAc (10 mL) was added PdCl₂ (30 mg) and themixture was stirred under a hydrogen balloon at rt for 3˜5 hrs. Afterfiltration, the filtrate was evaporated and the residue, was purified byprep HPLC to afford(3R)—N—((S)-3-cyclopentyl-1-(methylamino)propan-2-yl)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(36.2 mg, 46.5%). ¹H NMR (CD₃OD, 400 MHz) δ 0.89 (m, 1H), 1.12-2.15 (m,H), 2.58 (m, 2H), 2.71 (s, 3H), 2.93 (m, 1H), 3.15 (m, 3H), 3.23 (s,3H), 3.98 (m, 2H), 4.26 (m, 1H), 4.48 (m, 2H), 6.83 (m, 1H), 7.12 (m,1H), 7.21 (m, 1H).

Example 123(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide(I-247A)

Step 1.(3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide

A stirred solution of (2-(trimethylsilyl)ethyl)(S)-2-amino-3-cyclohexylpropyl-methylcarbamate (484 mg, 1.54 mmol) andCS₂ (96 μL, 1.62 mmol) in THF (5 mL) was cooled in an ice bath and asolution of NaOH (65 mg, 1.62 mmol) in water (0.15 mL) was added. Themixture was heated at reflux for 1.5 h, cooled to 40° C. and treatedwith ethyl chloroformate (0.155 mL, 1.62 mmol). The mixture was heatedat 40° C. for 30 min, cooled and poured into ether (90 mL). The etherlayer was washed with water (25 mL), brine (25 mL) and dried over MgSO₄.Removal of the solvent left an oil (660 mg). An aliquot of this oil (83mg) and(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (42mg, 0.13 mmol) were dissolved in MeCN (1 mL) and heated at 100° C. in amicrowave for 10 min. The mixture was concentrated to leave an oil whichwas applied to a 2-g silica SPE cartridge and eluted sequentially with0, 10, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to affordsix fractions. The third fraction was evaporated to afford(3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide(35 mg) as an oil.

Step 2.(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide

A solution of(3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide(35 mg, 52 μmol) and Et₄NF (40 mg, 0.26 mmol) in MeCN (1 mL) was heatedat 60° C. in a microwave for 10 min. The reaction mixture was submitteddirectly to prep HPLC to afford(3R)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide(6.4 mg, 23%) and recovered(3R)—N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide(11.2 mg).

Example 124

The following compound was prepared using procedures analogous to thosedescribed in Example 123:

Cpd. No. Name I-122AN-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((3-methoxypropoxy)(phenyl)methyl)piperidine-1-carbothioamide using3-((3-methoxypropoxy)(phenyl)methyl)piperidine in Step 1

Example 125(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine(I-271A)

Step 1. (2-(Trimethylsilyl)ethyl)(S)-3-cyclohexyl-2-isothiocyanatopropylmethylcarbamate

A stirred solution of (2-(trimethylsilyl)ethyl)(S)-2-amino-3-cyclohexylpropyl-methylcarbamate (484 mg, 1.54 mmol) andCS₂ (96 μL, 1.62 mmol) in THF (5 mL) was cooled in an ice bath and asolution of NaOH (65 mg, 1.62 mmol) in water (0.15 mL) was added. Themixture was heated at reflux for 1.5 h, cooled to 40° C. and treatedwith ethyl chloroformate (0.155 mL, 1.62 mmol). The mixture was heatedat 40° C. for 30 min, cooled and poured into ether (90 mL). The etherlayer was washed with water (25 mL), brine (25 mL) and dried over MgSO₄.Removal of the solvent left an oil (660 mg). An aliquot of this oil (354mg) was dissolved in MeCN (4 mL) and heated at 150° C. in a microwavefor 10 min. The mixture was concentrated to afford an oil (403 mg) whichwas purified by chromatography on a 12-g silica cartridge eluted withhexane/EtOAc gradient to afford (2-(trimethylsilyl)ethyl)(S)-3-cyclohexyl-2-isothiocyanatopropylmethylcarbamate (278 mg) as anoil.

Step 2.1-Cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)thiourea

To a stirred solution of (2-(trimethylsilyl)ethyl)(S)-3-cyclohexyl-2-isothiocyanatopropyl-methylcarbamate (190 mg, 0.53mmol) in ethanol (5 mL) was added solid sodium hydrogen cyanamide (38mg, 0.59 mmol). The mixture was stirred at rt for 2 d, diluted with 1:1sat'd aq NH₄Cl/H₂O (40 mL) and extracted with ether (2×60 mL). Thecombined ether extracts were dried over MgSO₄ and rotovaped to leave1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea(230 mg, quant) as a white solid.

Step 3.(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine

To a stirred solution of1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea(230 mg, 0.58 mmol) and(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (180mg, 0.58 mmol) in DMF (5 mL) was added EDC (0.17 g, 0.87 mmol). Themixture was stirred for 16 h at rt, diluted with ether (175 mL) andwashed with 5% aq HCl (2×50 mL) and brine (50 mL). The combined aqueouswashes were back extracted with ether. The combined ether extracts wereconcentrated to afford crude product (290 mg). The mixture was purifiedby prep HPLC to afford(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine(145 mg, 37%).

Step 4.(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine

A solution of(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine(145 mg, 0.21 mmol) and Et₄NF (160 mg, 1.1 mmol) in MeCN (5 mL) washeated at 100° C. in the microwave for 7 min. The reaction mixture wasdirectly submitted to prep HPLC to afford(3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine(16 mg, 14%).

Example 126(R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(I-354A)

Step 1. tert-Butyl(S)-1-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropan-2-ylcarbamate

To a stirred solution of(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (31mg, 0.10 mmol) and (S)-tert-butyl1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (40 mg,0.10 mmol) in MeCN (1 mL) and CH₂Cl₂ (1 mL) was added DIEA (50 μL, 0.28mmol). The mixture was stirred at rt for 20 h, diluted with ether (90mL), washed with 5% aq HCl (20 mL) and 1 M aq NaOH (20 mL) and driedover MgSO₄. Removal of the solvent left an oil (82 mg) which was appliedto a 2-g silica SPE cartridge which was eluted sequentially with 10, 25,50, 75 and 100% ethyl acetate in hexanes (15 mL of each) to afford 5fractions. The 4^(th) fraction was concentrated to afford tert-butyl(S)-1-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropan-2-ylcarbamate(29 mg, 49%) as an oil.

Step 2.(R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

tert-Butyl(S)-1-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropan-2-ylcarbamate(29 mg, 0.05 mmol) was dissolved in MeCN (5 mL) and 5% aq HCl (5 mL) wasadded. The mixture was stirred at rt overnight and solid K₂CO₃ wasadded. MeCN was removed on the rotary evaporator and the aqueous residuewas extracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried over Na₂SO₄ and evaporated to leave an oil (55.5 mg). PreparativeHPLC afforded(R)—N—((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(22.7 mg, 93%) as a solid.

Example 127

The following compounds were prepared using procedures analogous tothose described in Example 126:

Cpd. No. Name I-6A 3-((3-methoxypropoxy)(phenyl)methyl)-N-(2-amino-3-cyclohexylpropyl)piperidine-1-carboxamide using 3-((3-methoxypropoxy)(phenyl)methyl)piperidine in Step 1. I-83A3-((3-methoxypropoxy)(2-phenylphenyl)methyl)-N-((S)-2-amino-3-cyclohexylpropyl)piperidine-1-carboxamide using 3-(biphenyl-2-yl(3-methoxypropoxy)methyl)piperidine in Step 1. I-373A(R)-N-((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide using(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol in Step 1. I-377A(R)-N-((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(benzo[b]thiophen-4-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide using (S)-1-(benzo[b]thiophen-4-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol inStep 1. I-381A(RS)-N-((S)-2-amino-3-cyclohexylpropyl)-2-((RS)-1-(benzo[b]thiophen-7-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxamide using (RS)-1-(benzo[b]thiophen-7-yl)-5-methoxy-1-((RS)-morpholin-2-yl)pentan-1-olin Step 1. I-394A(3R)-N-((R)-2-amino-3-tert-butoxypropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-475A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-2-(methylamino)propyl)piperidine-1-carboxamide I-36A(3R)-N-((S)-2-amino-5-methoxy-4,4-dimethylpentyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-54A(3R)-N-((S)-2-amino-5-methoxy-4,4-dimethylpentyl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-472A(3R)-N-((S)-2-amino-5-methoxy-4,4-dimethylpentyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-477A(3R)-N-((2R,3S)-3-amino-4-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-477B(3R)-N-((2S,3S)-3-amino-4-cyclohexylbutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-492A(3R)-N-((S)-2-amino-3-(4,4-difluorocyclohexyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-503A (3R)-N-(2-amino-3-cyclopentylpropyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-504A(3R)-N-((2S)-2-amino-3-(tetrahydrofuran-2-yl)propyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-508A(3R)-N-(2-amino-3-(tetrahydro-2H-pyran-4-yl)propyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-511A(3R)-N-((S)-2-amino-3-(trans-3-methoxycyclobutyl)propyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-511B(3R)-N-((S)-2-amino-3-(cis-3-methoxycyclobutyl)propyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-512A(S)-N-((S)-2-amino-3-cyclohexylpropyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide I-512B(S)-N-((S)-2-amino-3-cyclohexylpropyl)-3-((R)-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)piperidine-1-carboxamide I-513A(3R)-N-((2S)-2-amino-3-(tetrahydrofuran-2-yl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamideI-515A (3R)-N-((S)-2-amino-4-phenylbutyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-520A(3R)-N-((S)-2-amino-4-cyclohexylbutyl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide I-527A(3R)-N-((S)-2-amino-3-(3-methoxycyclobutyl)propyl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

Example 128N—((S)-3-Cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)benzamide(I-114A)

Step 1. (S)-methyl3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoate

A mixture of mono-methyl isophthalate (0.3230 g, 1.79 mmol, 1.0 equiv),2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylmethylcarbamate(0.5573 g, 1.77 mmol, 0.99 equiv), EDC (0.6200 g, 1.8 equiv), HOBT(0.4035 g, 1.66 equiv), and DIEA (3.6 mL, 11 equiv) in CH₂Cl₂ (20 mL)was stirred at rt for 18 h. The reaction mixture was quenched with 10%aq Na₂CO₃, extracted with CH₂Cl₂ and dried over Na₂SO₄. After thesolvent was removed, the crude (S)-methyl3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoate(1.397 g) was used in the next step without further purification. LC-MS(3 min) t_(o)=2.29 min, m/z 499 (M+Na⁺), 449, 359.

Step 2.(S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoicacid

A mixture of (S)-methyl3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoate(1.397 g) and LiOH.H₂O (0.430 g, 10 mmol, 5.7 equiv) in THF (50 mL) andH₂O (10 mL) was vigorously stirred at rt for 23 h. The reaction mixturewas quenched with 2 N HCl (6 mL). After the organic solvent was removedin vacuo, the aqueous phase was extracted with CH₂Cl₂ (3×) and thecombined organic layers were dried over Na₂SO₄. The crude(S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoicacid (0.923 g) was used in the next step without further purification.LC-MS (3 min) t_(R)=2.06 min, m/z 485 (M+Na⁺), 435, 391. ¹³C NMR (100MHz, CDCl₃) δ 168.45, 166.95, 157.89, 135.27, 132.73, 132.34, 129.95,128.47, 128.42, 64.25, 52.86, 45.49, 40.59, 34.58, 34.26, 33.77, 33.13,26.46, 26.23, 26.11, 17.64, −1.61.

Step 3.(S)—N¹-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N³-methoxy-N³-methylisophthalamide

A mixture of(S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoicacid (0.923 g, 1.77 mmol, 1.0 equiv), obtained as described above,N,O-dimethylhydroxylamine hydrochloride (0.378 g, 2.2 equiv), EDC (0.600g, 1.8 equiv), HOBt (0.384 g, 1.6 equiv), and DIEA (3 mL, 9.7 equiv) inCH₂Cl₂ (20 mL) was stirred at rt for 3 d. The reaction mixture wasdiluted with brine and extracted with CH₂Cl₂ (3×). The combined organicextracts were dried over Na₂SO₄. After the solvent was removed, thecrude product was purified by chromatography on a 40-g silica gelcartridge eluted with a gradient from 0% to 40% EtOAc in hexanes to give(S)—N¹-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N³-methoxy-N³-methylisophthalamide(0.7388 g, 83%). TLC r_(f)=0.38 (50% EtOAc in hexanes); LC-MS (3 min)t_(R)=2.12 min, m/z 528 (MNa⁺), 506 (M+H⁺), 478; ¹H NMR (400 MHz, CDCl₃)δ 8.09 (s, 1H), 7.84 (dt, J=7.9, 1.5 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H),7.42 (t, J=7.8 Hz, 1H), 677 (d, J=8.2 Hz, 1H), 4.48-4.39 (m, 1H),4.11-3.97 (m, 2H), 3.72 (dd, J=14.3, 10.5 Hz, 1H), 3.54 (s, 3H), 3.33(s, 3H), 3.01 (dd, J=14.3, 4.1 Hz, 1H), 2.90 (s, 3H), 1.85-0.80 (m,15H), −0.06 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 169.03, 166.25, 158.12,134.41, 130.84, 128.80, 128.12, 126.89, 63.75, 61.06, 52.51, 46.78,40.64, 34.60, 34.35, 33.53, 33.15, 26.36, 26.13, 26.06, 17.56, −1.61.

Step 4.(S)—N-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide

To a solution of(S)—N¹-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-N³-methoxy-N³-methylisophthalamide(0.7361 g, 1.46 mmol, 1.0 equiv) in THF (15 mL) was added 1.45 M4-methoxybutylmagnesium chloride in THF (4 mL, 5.8 mmol, 4.0 equiv) at0° C. under N₂. After 2 h, the reaction mixture was quenched with 1 N aqHCl (15 mL) and extracted EtOAc (3×). The combined EtOAc extracts weredried over Na₂SO₄ and concentrated to afford crude(S)—N-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide(0.758 g), which was used in the next step without further purification.LC-MS (3 min) t_(R)=2.34 min, m/z 555 (M+Na⁺), 534, 505.

Step 5.(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide

A mixture of crude(S)—N-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide(0.310 g), and TFA (4 mL) was stirred at rt for 3 h. After the solventwas removed in vacuo, the crude product was purified by preparative HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min, flow rate 25 mL/min) to give 0.0382g of TFA salt of(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide.LC-MS (3 min) t_(R)=1.34 min, m/z 389 (M+H⁺), 372, 358. ¹H NMR (400 MHz,CD₃OD) δ 8.50 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J=7.6 Hz, 1H),7.97 (d, J=7.9 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 4.46-4.41 (m, 1H), 3.30(t, J=6.2 Hz, 2H), 3.18 (s, 3H), 3.09-2.95 (m, 2H), 2.97 (t, J=7.0 Hz,2H), 2.60 (s, 3H), 1.76-0.78 (m, 17H).

Step 6.N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)benzamide

A 50 mL round bottom flask was charged with the TFA salt of(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide(0.0357 g, 0.071 mmol) and THF (5 mL). The flask was evacuated andrefilled with N₂. The mixture was cooled in a dry ice-acetone bath and 1M phenylmagensium bromide in THF (4 mL, 4 mmol) was added. After 1 h,the cooling bath was removed and the reaction mixture was stirred at rtfor 5 h. The mixture was quenched with 10% aq Na₂CO₃ (10 mL) andextracted with CH₂Cl₂ (3×). The combined organic extracts were driedover Na₂SO₄. The crude product was purified by preparative HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%—+90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min, flow rate 25 mL/min) to give theTFA salt ofN—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)-benzamide(0.0342 g, 83%). LC-MS (3 min) t_(R)=1.47 min, m/z 467 (MH⁺); ¹H NMR(400 MHz, CD₃OD) δ 8.26 (d, J=8.2 Hz, 1H), 7.89-7.03 (m, 9H), 4.40-4.38(m, 1H), 3.23 (t, J=6.4 Hz, 2H), 3.15 (s, 3H), 3.06-2.91 (m, 2H), 2.584,2.579 (s, 3H), 2.23 (t, J=8.2 Hz, 2H), 1.74-0.78 (m, 17H).

Example 129

The following compounds were prepared using procedures analogous tothose described in Example 128:

Cpd. No. Name I-128AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-m-tolylpentyl)benzamide I-129AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-o-tolylpentyl)benzamide I-137AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)benzamide I-138AN-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(1-(4-fluorophenyl)-1-hydroxy-5-methoxypentyl)benzamide I-167A3-(1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)benzamide I-274AN-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-(3-(trifluoromethyl)phenyl)pentyl)benzamide

Example 130N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)-benzamide(I-106A)

Step 1.(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpent-1-enyl)benzamide

A mixture of the TFA salt ofN—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(1-hydroxy-5-methoxy-1-phenylpentyl)benzamide(0.0257 g, 0.0442 mmol) and TFA (2 mL) was stirred at rt for 20 h.Removal of the solvent in vacuo, afforded the crude TFA salt of(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpent-1-enyl)benzamide,which was used in the next step without further purification. LC-MS (3min) t_(R)=1.72 min, m/z 449 (M+H⁺).

Step 2.N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)benzamide

A 250 mL Parr shaker vessel was charged with the TFA salt of(S)—N-(1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpent-1-enyl)benzamide,obtained as described above, 10% Pd/C (0.140 g) and methanol. The vesselwas placed in a Parr hydrogenation shaker and pressurized/evacuated 3times with H₂ gas, then pressurized to 55 psi. The reaction vessel wasshaken for 5 h, then carefully vented. The contents were filteredthrough an HPLC filter. After the solvent was removed in vacuo, thecrude product was purified by preparative HPLC (Phenomenex® Luna 5μC18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 13 min, flow rate 25 mL/min) to give the TFA salt ofN—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(5-methoxy-1-phenylpentyl)benzamide.LC-MS (3 min) t_(R)=1.67 min, m/z 451 (M+H⁺); ¹H NMR (400 MHz, CD₃OD) δ8.29 (d, J=8.2 Hz, 1H), 7.71-7.05 (m, 9H), 4.43-4.41 (m, 1H), 3.91 (t,J=7.9 Hz, 1H), 3.26 (t, J=6.4 Hz, 2H), 3.18 (s, 3H), 3.10-2.92 (m, 2H),2.616, 2.613 (s, 3H), 2.06-2.00 (m, 2H), 1.77-0.81 (m, 17H).

Example 131

Example omitted.

Example 132(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-340A)

(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(70 mg, 0.133 mmol) was mixed with isobutyronitrile (8 mL) and concH₂SO₄ (23 drops). After stirring vigorously overnight at rt, the mixturewas neutralized with K₂CO₃ (ca. 100 mg). A few drops of water were addedand the mixture was filtered. The filtrate was concentrated and theresidue was purified by preparative HPLC to afford(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(11.4 mg, 14%) as a TFA salt. ¹H NMR (400 MHz, CDCl₃): 7.94 (s, 1H),7.41 (td, 1H), 7.27 (td, 1H), 7.15 (t, 1H), 4.25 (d, 1H), 4.11 (m, 1H),3.92 (d, 1H), 3.37 (t, 1H), 3.28 (s, 3H), 3.07 (dd, 1H), 2.96 (dd, 1H),2.71 (s, 3H), 2.66 (m, 1H), 2.54 (td, 1H), 1.14 (dd, 6H). 3 min. LC-MS:R/T 1.59 min., m/z 596 (M+H⁺). In addition,(3R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideand(S)-3-(1-(3-chloro-2-fluorophenyl)-5-methoxypent-1-enyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamidewere isolated.

Example 133

The following compounds were prepared using procedures analogous tothose described in Example 132:

Cpd. No. Name I-272A(3R)-3-((S)-1-acetamido-1-(3-fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-301A(3R)-3-((S)-1-acetamido-1-(3-chlorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-322A(3R)-3-((S)-1-(3-chlorophenyl)-5-methoxy-1-(propionamido)pentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamideI-329A(3R)-3-((R)-1-acetamido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1- carboxamideI-329B(3R)-3-((S)-1-acetamido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1- carboxamideI-332A(3R)-3-(1-(3-chlorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-336A(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-(propionamido)pentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-340A(3R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-431A3-(1-acetamido-1-(3-chlorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide I-454A(R)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-((S)-1-(2,3-difluorophenyl)-5-methoxy-1-propionamidopentyl)piperidine-1- carboxamideI-458A2-(1-acetamido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)morpholine-4-carboxamide I-469A(R)-3-((S)-1-butyramido-1-(3-chloro-2-fluorophenyl)-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamideI-553A(3R)-3-((S)-1-acetamido-5-ethoxy-1-(3-fluorophenyl)pentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-558A(3R)-3-((S)-1-acetamido-1-(3-chlorophenyl)-5-ethoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Example 134(3R)-3-((S)-1-(3-Chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-155A)

Step 1.(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

A 100 mL round-bottom flask was charged with of(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide(0.6557 g, 1.0 mmol, 1.0 equiv), n-Bu₄NI (3.765 g, 10 mmol, 10 equiv),and CH₃CN (15 mL). To the flask was added AlCl₃ (1.345 g, 10 mmol, 10equiv) at 0° C. After 4 h, the reaction mixture was quenched with 10% aqNa₂CO₃ (18 mL) and 1 N aq NaOH (10 mL) and extracted with CH₂Cl₂ (3×).The combine organic extracts were dried over Na₂SO₄ and the solvent wasremoved in vacuo. The crude product was treated with Teoc-OSu (0.534 g,2.06 mmol), K₂CO₃ (4.080 g, 29.5 mmol), water (5 mL) and CH₂Cl₂ (50 mL)at rt for 2.5 h. The mixture was diluted with brine, extracted withCH₂Cl₂ and dried over Na₂SO₄. After the solvent was removed in vacuo,the crude product was purified by prep HPLC (Phenomenex® Luna 5μ C18(2)100 A, 250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 10 min, flow rate 25mL/min) to give(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(0.1625 g). LC-MS (3 min) t_(R)=2.29 min, m/z 660, 662 (MNa⁺), 638, 640(MH⁺).

Step 2.(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

A 50 mL, round-bottom flask was charged with(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide(0.1081 g, 0.1693 mmol), Et₄NF (0.6045 g), and acetonitrile (8 mL). Thereaction mixture was stirred at 80° C. for 2 h and then purified by prepHPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%—90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min, flow rate 25 ml/min) to give thetrifluoroacetate salt of(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)-propan-2-yl)piperidine-1-carboxamide.LC-MS (3 min) t_(R)=1.40 min, m/z 494, 496 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 7.33-7.32 (m, 1H), 7.21-7.09 (m, 3H), 4.19 (d, J=11.7 Hz, 1H),4.06-3.98 (m, 1H), 3.86 (d, J=12.9 Hz, 1H), 3.37 (t, J=6.6 Hz, 2H), 2.95(dd, J=12.6, 3.2 Hz, 1H), 2.83 (dd, J=12.6, 10.0 Hz, 1H), 2.59 (s, 3H),2.47-2.41 (m, 2H), 1.92-0.74 (m, 24H); ¹³C NMR (100 MHz, CD₃OD) δ159.94, 148.89, 135.14, 130.38, 127.44, 127.33, 125.43, 78.43, 62.77,56.01, 47.58, 47.02, 46.89, 45.87, 40.89, 40.47, 35.44, 34.89, 34.03,33.88, 33.38, 27.54, 27.31, 26.64, 26.50, 20.95.

Example 135

The following compound was prepared using procedures analogous to thosedescribed in Example 134:

Cpd. No. Name I-348A(R)-3-((S)-1-(3-chlorophenyl)-1,4-dihydroxybutyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1- carboxamide

Example 136(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-191A)

Step 1.(3R)-3-((S)-1-(3-chlorophenyl)-4-formyl-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

A 100 mL, round-bottom flask was charged with(3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide(0.0544 g (0.0852 mmol), DMSO (2.5 mL) and Et₃N (1 mL). The flask wascooled in an ice bath and a mixture of pyridine-sulphur trioxide complex(0.24 g, 1.51 mmol) and dry DMSO (2.5 mL) was added. After 10 min, theice bath was removed. The reaction mixture was allowed to stir at rt for3 h. The mixture was quenched with brine, extracted with EtOAc (3×) anddried over Na₂SO₄. Removal of the solvent left crude(3R)-3-((S)-1-(3-chlorophenyl)-4-formyl-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(0.1036 g), which was carried on to the next step without furtherpurification. LC-MS (3 min) t_(R)=2.43 min, m/z 658, 660 (MNa⁺), 636(MH⁺), 618, 620.

Step 2.(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

To a solution of crude(3R)-3-((S)-1-(3-chlorophenyl)-4-formyl-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide,obtained as described above, in THF (5 mL) was added methylmagnesiumchloride (3 M in THF, 5 mL, 15 mmol) at −78° C. under N₂. After 17 h,the mixture was quenched with 10% aq Na₂CO₃ (3 mL), extracted (3×) withCH₂Cl₂ (3×) and dried over Na₂SO₄. The crude product was treated withTeoc-OSu (0.0785 g, 0.30 mmol) and K₂CO₃ (0.760 g) in H₂O/CH₂Cl₂. Theproduct was purified by preparative HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOH over 8 minand then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 18.5 min, flow rate 25 mL/min)to give(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(0.0028 g). LC-MS (3 min) t_(R)=2.36 min, m/z 674, 676 (MNa⁺), 652, 650(MH⁺).

Step 3.(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

A 50 mL, round-bottom flask was charged with(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide,Et₄NF (0.2274 g) and MeCN (4 mL). The reaction mixture was stirred at80° C. for 2.5 h and then purified by prep HPLC (Phenomenex® Luna 5μC18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 13 min, flow rate 25 mL/min) to give the TFA salt of(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyhexyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide.LC-MS (3 min) t_(R)=1.53 min, m/z 508, 510 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 7.36-7.34 (m, 1H), 7.24-7.13 (m, 3H), 4.20 (d, J=15 Hz, 1H),4.06-3.99 (m, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.58-3.53 (m, 1H), 2.97 (dd,J=12.8, 3.1 Hz, 1H), 2.82 (dd, J=12.6, 10.2 Hz, 1H), 2.61 (s, 3H),2.49-2.41 (m, 2H), 0.987, 0.982 (d, J=6 Hz, 3H), 1.94-0.80 (m, 24H).

Example 137

The following compound was prepared using procedures analogous to thosedescribed in Example 136:

Cpd. No. Name I-235A(3R)-3-((1S)-1-(3-chlorophenyl)-1,5-dihydroxyheptyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1- carboxamide

Example 139(3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-357A)

Step 1.(3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide

To a stirred mixture of(3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(40.0 mg, 0.06 mmol) in DMF (0.5 mL), was added CuCN (excess), and theresulting solution was heated in a CEM microwave reactor at 220° C. for20 min. The mixture was cooled to rt, and purified by preparative HPLCto give(3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide(8.0 mg, 22%). MS m/z 665 (M+Na⁺).

Step 2.(3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

To a solution(3R)-3-((S)-1-(3-cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(8.0 mg, 0.012 mmol) in acetonitrile (1.0 mL) was added Et₄NF (excess).The resulting solution was stirred at 50° C. until no starting materialremained (˜1 h). Solvent was removed under vacuum and the residue waspurified by preparative HPLC to give the TFA salt of(3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(4.0 mg, 52%). ¹H NMR (400 MHz, CD₃OD): 7.78 (s, 1H), 7.68 (d, 1H), 7:62(d, 1H), 7.56 (dd, 1H), 4.34 (d, 1H), 4.14 (m, 1H), 3.98 (d, 1H), 3.30(t, 2H), 3.24 (s, 3H), 3.06 (dd, 1H), 2.94 (dd, 1H), 2.72 (s, 3H), 2.54(m, 2H), 1.18-2.06 (m, 21H), 0.84-1.10 (m, 3H); MS m/z 499 (M+H⁺).

Example 140

The following compound was prepared using procedures analogous to thosedescribed in Example 139:

Cpd. No. Name I-379A (R)-3-((S)-1-(2-cyano-5-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide

Example 141 Methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate(I-412A)

Step 1. Methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxy-carbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate

Triethylamine (50 μL) was added to a stirred suspension of(3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide(21.0 mg, 0.03 mmol), Pd(dppf)Cl₂ (5 mg) and Pd(PPh₃)₄ (5 mg) in 4:1DMF/MeOH (2 mL). A carbon monoxide atmosphere was established in thereaction vessel and the mixture was stirred at 70° C. overnight. Aftercooling to ambient temperature, the mixture was extracted with EtOAc(2×5 mL) and the combined organic layers were washed with 1 N aq HCl(2×1 mL) and concentrated. The residue was purified by preparative HPLCto give methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)-piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate(5.4 mg, 27%). MS m/z 698 (M+Na⁺).

Step 2. Methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)-piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate

To a solution of the above methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate(5.4 g, 0.008 mmol) in acetonitrile (1.0 mL) was added Et₄NF (excess).The resulting solution was stirred at 50° C. until no starting materialremained (˜1 h). Solvent was removed under vacuum, and the residue waspurified by preparative HPLC to give the TFA salt of methyl3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate(2.2 mg, 59%). ¹H NMR (400 MHz, CD₃OD): 8.06 (s, 1H), 7.90 (d, 1H), 7.62(d, 1H), 7.44 (dd, 1H), 4.32 (d, 1H), 4.14 (m, 1H), 3.98 (d, 1H), 3.92(s, 3H), 3.30 (t, 2H), 3.24 (s, 3H), 3.04 (dd, 1H), 2.93 (dd, 1H), 2.70(s, 3H), 2.54 (m, 2H), 1.18-2.06 (m, 21H), 0.84-1.14 (m, 3H); MS m/z 532(M+H⁺).

Example 142(1S)-1-(3-chlorophenyl)-2-(2-methoxyethoxy)-1-((3R)-piperidin-3-yl)ethanol

Step 1. (3R)-tert-butyl3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate

A flame dried 250 mL round bottom flask was charged with sodium hydride(60% in oil, 1.45 g, 36.2 mmol) and trimethyloxosulfonium iodide (8.05g, 36.5 mmol). The flask was evacuated and refilled with N₂. Dry DMSO(50 mL) was added and the mixture was stirred at rt for 1 h. A portionof this solution (14.5 mL, 10.5 mmol, 1.5 equiv) was added by syringe toa 150 mL round bottom flask which had been charged with (R)-tert-butyl3-(3-chlorobenzoyl)-piperidine-1-carboxylate (2.27 g, 7 mmol) and THF(30 mL) and placed under N₂. The resulting mixture was stirred for 1 hat rt. The reaction mixture was quenched with brine and extracted withEtOAc (3×). The combined organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to give (3R)-tert-butyl3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate as a mixtureof two isomers (2.32 g, 6.9 mmol, 99% yield), which was used in the nextstep without further purification. ¹H NMR (400 MHz, CDCl₃): 1.40 (s,9H), 1.55-1.72 (m, 3H), 1.85 (m, 1H), 2.01 (m, 1H), 2.35-2.60 (m, 2H),2.65 (d, 1H), 3.063 (d, 1H), 4.05 (m, 1H), 4.15 (m, 1H), 7.26 (m, 3H),7.34 (s, 1H); MS (E/Z): 338 (M+H⁺)

Step 2. (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine-1-carboxylate

A stirred solution of BF₃.Et₂O (12.9 mg, 0.0592 mmol) and NaH (22.6 mg,0.296 mmol) in 2-methoxyethanol (10 mL) was warmed to 55-60° C. and(3R)-tert-butyl3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate (100 mg, 0.296mmol) was added dropwise. After addition, the reaction mixture wasstirred at the same temperature overnight. The reaction mixture wasconcentrated and the residue was partitioned between H₂O and EtOAc. Theorganic layer washed with water and brine, dried over Na₂SO₄, filteredand concentrated in vacuo. LC-MS analysis of the crude product indicatedthe presence of two isomers. The crude product was purified bypreparative HPLC to give the major isomer (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine-1-carboxylate(30 mg, 0.073 mmol); ¹H NMR (400 MHz, CDCl₃): 1.33 (s, 9H), 1.65 (m,1H), 1.74 (m, 1H), 1.96 (m, 1H), 2.47 (m, 2H), 3.26 (m, 2H), 3.33 (s,3H), 3.46 (m, 2H), 3.61 (m, 2H), 3.79 (m, 1H), 3.84 (m, 1H), 3.99 (m,1H), (m, 1H), 7.22 (m, 3H), 7.42 (s, 1H); MS (E/Z): 414 (M+H⁺)

The minor isomer (R)-tert-butyl3-((R)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine-1-carboxylatewas also isolated (25 mg, 0.061 mmol). ¹H NMR (400 MHz, CDCl₃): 1.26 (m,2H), 1.45 (s, 9H), 1.57 (m, 1H), 1.76 (m, 1H), 2.51 (m, 2H), 3.27 (m,2H), 3.33 (s, 3H), 3.47 (m, 2H), 3.62 (m, 2H), 3.80 (m, 1H), 3.87 (m,1H), 4.01 (m, 1H), 4.33 (m, 1H), 7.24 (m, 3H), 7.40 (s, 1H); MS (E/Z):414 (M+H⁺)

Step 3.(1S)-1-(3-chlorophenyl)-2-(2-methoxyethoxy)-1-((3R)-piperidin-3-yl)ethanol

A solution of (R)-tert-butyl3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)-ethyl)piperidine-1-carboxylate(30 mg, 0.073 mmol) in 20% TFA/CH₂Cl₂ (5 mL) was stirred at 0° C. for 30min. Evaporation of the solvent afforded(1S)-1-(3-chlorophenyl)-2-(2-methoxy-ethoxy)-1-((3R)-piperidin-3-yl)ethanol(30 mg, 0.073 mmol 100%). MS (E/Z): 314 (M+H⁺).

Example 143 (R)-tert-Butyl3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

Step 1.3-((S)-1-((R)-1-(tert-Butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxy-pentyl)benzoicacid

To a solution of (R)-tert-butyl3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxy-pentyl)piperidine-1-carboxylate(279.1 mg, 0.61 mmol) in THF (5 mL) at −70° C. was added t-butyllithiumin pentane (1.7 M, 0.71 mL, 1.22 mmol) dropwise. When the addition wascomplete dried carbon dioxide was bubbled through the reaction systemfor 10 min, and completion of reaction was confirmed by LC-MS. Thesolution was warmed to rt, and sat'd aq Na₂CO₃ solution (5 mL) wasadded. The organic layer was separated, and washed once with 1 N NaOH (2mL). The combined aqueous solutions were acidified with 1 N aq HCl andextracted with EtOAc (5×5 mL). The organic layer was dried over Na₂SO₄,and concentrated under vacuum to give3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxy-pentyl)benzoicacid (152.4 mg, 59%) as a white solid. MS m/z 422 (M+H⁺).

Step 2. (R)-tert-Butyl3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate

To a solution of3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoicacid (51.0 mg, 0.12 mmol) in CH₂Cl₂ (2 mL) was added oxalyl chloride(17.3 mg, 0.13 mmol) followed by DMF (1 drop). The resulting mixture wasstirred until gas evolution ceased (˜10 min), and completion of reactionwas confirmed by LC-MS. To the reaction flask was added excess NH₄OH,and reaction was stirred at rt for another 10 min. Water (5 mL) wasadded and organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂ (2×5 mL) and the combined organic layers were washed withbrine (5 mL), dried over Na₂SO₄, and concentrated under vacuum to give(R)-tert-butyl3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate(26.2 mg, 52%). MS m/z 443 (M+Na⁺).

Example 144 (S)-tert-butyl1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate

Step 1. (S)-tert-butyl1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate

To a stirred mixture of (S)-2-(trimethylsilyl)ethyl2-amino-3-cyclohexylpropylcarbamate (4.61 g, 15.4 mmol), dioxane (50 mL)and 10% aq K₂CO₃ (50 mL) was added solid Boc₂O (3.50 g, 15.4 mmol). Themixture was stirred at rt for 18 h. Dioxane was removed on the rotaryevaporator and the aqueous residue was extracted with ether (175 mL).The ether layer was washed with 5% aq HCl (50 mL), satd aq NaHCO₃ (50mL) and brine (50 mL) and dried over MgSO₄. Removal of the solventafforded (S)-tert-butyl1-(2-(trimethylsilyl)ethoxycarbonyl-amino)-3-cyclohexylpropan-2-ylcarbamate(6.55 g, quant) as a yellow oil.

Step 2. (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate

To a stirred solution of (S)-tert-butyl1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate(6.55 g, 15.4 mmol) in MeCN (100 mL) was added Et₄NF (7.5 g, 50 mmol).The mixture was stirred overnight at rt and at 60° C. for 7 h. Themixture was concentrated and the oily residue was taken up in EtOAc (175mL). The mixture was washed with water (2×50 mL) and brine (50 mL) anddried over Na₂SO₄. Removal of the solvent afforded (S)-tert-butyl1-amino-3-cyclohexylpropan-2-ylcarbamate (3.39 g, 80%) as a syrup.

Step 3. (S)-tert-butyl1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate

To a stirred solution of (S)-tert-butyl1-amino-3-cyclohexylpropan-2-ylcarbamate (0.65 g, 2.54 mmol) in MeCN (20mL) and THF (5 mL) was added powdered NaHCO₃ (0.43 g, 5.08 mmol)followed by a solution of p-nitrophenyl chloroformate (0.51 g, 5.08mmol) in MeCN (20 mL) dropwise over 10 min. The mixture was stirred atrt for 2 h, filtered through a pad of Celite and concentrated to leave awhite solid. This material was purified by chromatography on a 40-gsilica cartridge eluted with a gradient from 0-100% EtOAc in hexanes toafford (S)-tert-butyl1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (0.67g, 67%) as an off-white solid.

Example 1453-((2-acetamidoethoxy)(phenyl)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide(I-112A)

A mixture of the TFA salt ofN—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)-3-(hydroxy)(phenyl)methyl)benzamide(0.0160 g, 0.0323 mmol), N-(2-hydroxyethyl)acetamide (0.1570 g, 1.52mmol), p-toluenesulfonic acid monohydrate (0.1158 g, 0.61 mmol) andtoluene (1.5 mL) was heated at 140° C. for 2 h. After the solvent wasremoved in vacuo, the crude product was purified by reversed-phase HPLC(Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90%CH₃CN/H₂O, 0.1% CF₃COOH over 13 min, flow rate 25 mL/min) to give theTFA salt of3-((2-acetamidoethoxy)(phenyl)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)benzamide(0.0061 g). LC-MS (3 min) t_(R)=1.37 min, m/z 466 (MH⁺); ¹H NMR (400MHz, CD₃OD) δ 8.34-8.29 (m, 1H), 7.86-7.12 (m, 9H), 5.76 (s, 1H), 5.41(d, J=2 Hz, 1H), 4.45-4.38 (m, 1H), 3.44 (t, J=5 Hz, 2H), 3.35-3.31 (m,2H), 3.10-3.06 (m, 1H), 3.00-2.93 (m, 1H), 2.62 (s, 3H), 1.844, 1.839(s, 3H), 1.77-0.82 (m, 13H).

Example 146

The following compound was prepared using procedures analogous to thosedescribed in Example 145:

Cpd. No. Name I-326A (3R)-3-(1-(3-hydroxypropoxy)-1-(3-chlorophenyl)-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide

Example 147 7-bromo-2-methylbenzofuran

A stirred solution of 7-bromobenzofuran (493 mg, 2.5 mmol) in dry THF (5mL) was cooled to −70° C. and 2M LDA in 1:1 THF/heptane (1.4 mL, 2.8mmol) was added dropwise over 2 min. The mixture was stirred at −70° C.for 1 h and methyl iodide (0.19 mL, 3.0 mmol) was added. The mixture wasstirred at −70° C. for 3 h and at 0° C. for 1 h. The mixture was pouredinto 5% aq HCl (60 mL) and extracted with ether (2×50 mL). The combinedether extracts were washed with sat'd aq NaHCO₃ (20 mL) and dried overMgSO₄. Removal of the solvent left an oil (470 mg) which was purified bychromatography on a 40-g silica cartridge eluted with hexanes to afford7-bromo-2-methylbenzofuran (277 mg, 52%, estimated purity ˜80%).

Example 148 7-bromo-2-isobutylbenzofuran

A stirred mixture of 2,6-dibromophenol (946 mg, 3.76 mmol), Cu₂O (322mg, 2.25 mmol), 4-methylpentyne (0.5 mL, 3.9 mmol) and pyridine (5 mL)was heated at vigorous reflux for 0.5 h. The mixture was concentratedunder reduced pressure to remove pyridine, diluted with ether (100 mL),washed with water (50 mL), 5% aq HCl (2×50 mL) and 1M aq NaOH (50 mL)and dried over MgSO₄. Removal of the solvent left an oil (650 mg)containing 7-bromo-2-isobutylbenzofuran (˜70% pure).

Example 149

(3R)-3-(1-(3-chloro-2-fluorophenyl)-1-fluoro-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-478A) was prepared by procedures analogous to those described inExample 43.

Example 150

(3R)—N-((2S,3S)-3-amino-4-cyclohexyl-1-hydroxybutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(I-488A) was prepared by procedures analogous to those described inExample 112.

Example 151

(3R)-3-((S)-1-(2,3-dihydrobenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-((1r,4S)-4-fluorocyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-480A) was prepared by procedures analogous to those described inExample 122.

Example 152

(R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

To a stirred, ice-cold solution of(R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol)in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol) understirring. The mixture was stirred for 1 h in the ice-water bath. Asuspension of triethylamine (207 mL, 1.41 mol) andN,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900mL) was added. The reaction mixture was allowed to warm to rt andstirred overnight. Tlc showed the reaction was complete. Solvent wasevaporated, and the residue was dissolved in CH₂Cl₂ (1.2 L), washedsuccessively with 0.5 N aq HCl, satd aq Na₂CO₃ and brine, dried overNa₂SO₄ and evaporated to give (R)-tert-butyl3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 90.6%),which was used in the next step directly without further purification.Chiral HPLC indicated that the product had an enantiomeric excess of96%˜98%. ¹H NMR (400 MHz, CDCl₃): 4.05-4.19 (m, 2H), 3.71 (s, 3H), 3.16(s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m,2H), 1.44 (s, 9H).

Example 153(3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide(I-56A)

tert-butyl 3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate (29mg, 0.079 mmol) was added to an acetonitrile (2 mL) solution of5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol (28 mg,0.076 mmol), diisopropylamine (20 μL, 0.11 mmol), and DMAP (10 mg, 0.084mmol). The reaction was allowed to stir overnight at rt. The solvent wasevaporated and the crude material was redissolved in methylene chloride.The solution was washed with 1 N aq NaOH, 1 M aq HCl and brine. Theorganic layer was separated and the solvent was evaporated. The crudematerial was dissolved in acetonitrile (9 mL) and treated with 2 M aqHCl (9 mL). The reaction was allowed to stir overnight. The solvent wasevaporated and the crude mixture purified by preparative HPLC to give(3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(piperidin-3-yl)piperidine-1-carboxamideas its TFA salt (38.7 mg). MS ESI +ve m/z 496 (M+1).

Example 154(3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide(I-523A)

Step 1. (S)-tert-Butyl3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate

To a stirred solution 4-nitrophenyl chloroformate (26.0 mg, 0.13 mmol)in anhydrous CH₂Cl₂ was added a solution of (S)-tert-butyl3-aminopiperidine-1-carboxylate (27.0 mg, 0.13 mmol) and pyridine (7 μL)in CH₂Cl₂ (0.5 mL). The mixture was stirred for 30 min. LC-MS showedcomplete conversion. This intermediate was used as a solution for thenext step.

Step 2. (S)-tert-Butyl3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate

A solution of(S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olTFA salt (62.7 mg, 0.13 mmol) in anhydrous CH₂Cl₂ (0.5 mL) containingtriethyl amine (0.1 mL) was added to above solution of (S)-tert-butyl3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate within 1 min.The mixture was stirred for 30 min. The reaction mixture was evaporatedand the residue was purified by preparative HPLC to afford(S)-tert-Butyl3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate(35 mg). MS m/z 612 (M+H)⁺.

Step 3.(3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide

(S)-tert-Butyl3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate(20 mg, 0.033 mmol) was dissolved in TFA/dichloromethane (1 mL, 1:3,v/v), stirred 20 min, evaporated, and purified by preparative HPLC togive the(3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide(9.39 mg) as its TFA salt. ¹H NMR (400 MHz, CD₃OD): δ ppm 7.57 (d, J=8.4Hz, 1H), 7.36-7.20 (m, 3 H), 7.04-7.02 (m, 2H), 6.92 (m, 1H), 4.03 (m,1H), 3.85-3.75 (m, 2H), 3.39-3.32 (m, 3 H), 3.29 (s, 3H), 2.86 (m, 1H),2.71-2.56 (m, 3H), 2.37, 2.35 (two s, 3H, rotamer), 1.99 (m, 2H),1.88-1.26 (m, 13H), 0.92 (m, 1H). MS m/z 512 (M+H)⁺.

Example 155

The following compounds were prepared using procedures analogous tothose described in Example 154:

-   (3R)—N-(azetidin-3-ylmethyl)-3-((S)-1-(3-fluoro-2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide    (I-525A)

Example 156 (3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate

Step 1. Benzyl 5,6-dihydropyridine-1(2H)-carboxylate

A solution of 1,2,3,6-tetrahydropyridine (5.0 g, 60.15 mmol) andtriethylamine (16.77 mL, 2 equiv) in CH₂Cl₂ (50 mL) was cooled to 0° C.(ice/water bath), Benzyl chloroformate (9.7 mL, 1.1 equiv) was addedslowly. After 30 min, the reaction mixture was allowed to warm slowly tort and stirred for 4 h. LC-MS showed the reaction was complete. Themixture was diluted with ether (300 mL), washed with 5% aq HCl (2×50mL), satd aq NaHCO₃ (40 mL) and brine (40 mL), and dried over Na₂SO₄.After concentration, benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93g, 78% yield) was left. LC-MS (3 min) t_(R)=1.74 min., m/z 218 (M+1).

Step 2. Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

A solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93 g,45.76 mmol) in CH₂Cl₂ (75 mL) was cooled to 0° C. (ice/water bath),Solid m-chloroperoxybenzoic acid (77%, 15.38 g, 1.5 equiv) was added.After 10 min, the reaction mixture was warmed slowly to rt. A whiteprecipitate formed after 1 h. After stirring for another 1 h, LC-MSshowed the reaction was complete. The mixture was diluted with ether(300 mL), washed by with 5% aq NaOH (2×40 mL), 25% aq Na₂S₂O₃ solution(3×20 mL) and brine (30 mL), and dried over Na₂SO₄. After concentration,the residue was purified by flash chromatography (120 g silica gelcolumn, 12%-70% EtOAc in hexanes gradient, 2^(nd) UV peak) to affordbenzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7.87 g, 74%yield). LC-MS (3 min) t_(R)=1.41 min., m/z 234 (M+1).

Step 3. (±)-(3R,4R)-Benzyl 3-azido-4-hydroxypiperidine-1-carboxylate

Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (6.78 g, 29.1mmol), sodium azide (3.78 g, 2 equiv), and ammonium chloride (1.56 g, 1equiv) were dissolved in methanol (100 mL) and water (20 mL). Themixture was heated at 65° C. for 18 h. The mixture was cooled to rt andmethanol was removed under vacuum. The aqueous residue was extractedwith ether (3×120 mL). The combined ether layers were washed with brine(30 mL) and dried over Na₂SO₄. Concentration afforded (3R,4R)-benzyl3-azido-4-hydroxypiperidine-1-carboxylate (8.07 g, quant.) which wasused for without further purification. LC-MS (3 min) t_(R)=1.45 min.,m/z 277 (M+1).

Step 4. (±)-(3R,4R)-Benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate

(3R,4R)-benzyl 3-azido-4-hydroxypiperidine-1-carboxylate (8.07 g, 29.1mmol) and pyridine (6 mL, 2.55 equiv) were dissolved in CH₂Cl₂ (20 mL)and cooled to 0° C. (ice/water bath). Solid p-TsCl (11.1 g, 2.1 equiv)was added. After 5 min, the reaction mixture was allowed to warm to rtslowly and stirred overnight. LC-MS showed the reaction was complete.The mixture was diluted with ether (300 mL), washed with 5% HCl (3×35mL), satd aq NaHCO₃ (40 mL) and brine (30 mL), and dried over Na₂SO₄.After concentration, the residue was purified by flash chromatography(120 g silica gel column, 0-50% EtOAc in hexanes gradient, 2^(nd) UVpeak) to afford (3R,4R)-benzyl3-azido-4-(tosyloxy)piperidine-1-carboxylate (12.18 g, 97%). LC-MS (3min) t_(R)=1.99 min., m/z 431 (M+1).

Step 5. (±)-(3R,4R)-benzyl 3-amino-4-(tosyloxy)piperidine-1-carboxylate

To a cooled (0° C., ice/water bath) solution of CuSO₄.5H₂O (642 mg, 0.5equiv) in methanol (30 mL) was added slowly NaBH₄ (200 mg, 1.05 equiv).To the stirred black suspension was added a solution of (3R,4R)-benzyl3-azido-4-(tosyloxy)piperidine-1-carboxylate (2.21 g, 5.14 mmol) inmethanol (20 mL). Additional NaBH₄ (578 mg, 3 equiv) was introduced intothe reaction in four portions over the course of 1 h. LC-MS showed thereaction was complete. The reaction mixture was filtered through a padof Celite, and concentrated. The residue was diluted with CH₂Cl₂ (70mL), washed with water (15 mL), satd aq NH₄Cl solution (2×10 mL) andbrine (15 mL), and dried over Na₂SO₄. Concentration afforded(3R,4R)-benzyl 3-amino-4-(tosyloxy)piperidine-1-carboxylate (1.34 g,64%). LC-MS (3 min) t_(R)=1.26 min., m/z 405 (M+1). The product was usedfor the next step without further purification.

Step 6. (±)-(1R,6S)-3-benzyl 7-tert-butyl3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylate

(3R,4R)-benzyl 3-amino-4-(tosyloxy)piperidine-1-carboxylate (274 mg,0.678 mmol) and DIEA (177 μL, 1.5 equiv) were dissolved in methanol (8mL) and heated to 80° C. for 20 min in a CEM Microwave reactor. LC-MSshowed the reaction was complete. The reaction mixture was concentratedand redissolved in CH₂Cl₂ (10 mL). (Boc)₂O (150 mg, 1 equiv) was addedand the mixture was stirred overnight at rt. LC-MS showed the reactionwas complete. The reaction mixture was concentrated and purified byflash chromatography (40 g silica gel column, 0˜45% EtOAc in hexanesgradient, major UV peak) to afford (1R,6S)-3-benzyl 7-tert-butyl3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylate (227 mg, quant). LC-MS(3 min) t_(R)=1.86 min., m/z 355 (M+Na).

Step 7. (±)-(3S,4S)-benzyl3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate

(1R,6S)-3-benzyl 7-tert-butyl3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylate (220 mg, 0.663 mmol),CuI (25 mg, 0.2 equiv), and a stirring bar were put in a 100-mL flask.The flask was evacuated and backfilled with N₂ gas (3×). Dry THF (5 mL)was added and the mixture was cooled to −40° C. 1 M Cyclohexylmagnesiumbromide in THF (2.0 mL, 3 equiv) was added slowly. After 8 min, thereaction mixture was allowed warmed slowly to rt. After 20 min, thereaction mixture turned into black. After stirring a further 2 h, LC-MSshowed the reaction was complete. Satd aq NH₄Cl solution (5 mL) wasadded to quench the reaction. The reaction mixture was partitionedbetween EtOAc (50 mL) and satd aq NH₄Cl solution (20 mL). The aqueouslayer was extracted with EtOAc (20 mL). The combined EtOAc layers werewashed with water (15 mL) and brine (15 mL), and dried over Na₂SO₄.After concentration, the residue was purified by preparative HPLC toafford (3S,4S)-benzyl3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate (62.3mg, 23% yield) and (3S,4S)-benzyl4-(tert-butoxycarbonylamino)-3-cyclohexylpiperidine-1-carboxylate (15mg). LC-MS (3 min) t_(R)=2.33 min., m/z 439 (M+Na).

Step 8. (±)-(3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate

(3S,4S)-benzyl3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate (35mg, 0.084 mmol) was dissolved in 1:1 2N aq HCl/acetonitrile (8 mL) andstirred overnight at rt. LC-MS showed the reaction was complete. Thereaction mixture was basified with 5% aq NaOH solution to about pH=9.The acetonitrile was removed under vacuum. The aqueous residue wasextracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washedwith brine (10 mL) and dried over Na₂SO₄. Concentration afforded(3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate (23 mg, 86%yield). The crude product was used in the next step without furtherpurification. LC-MS (3 min) t_(R)=1.31 min., m/z 317 (M+1).

Example 157(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3RS,4RS)-4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide(I-544A)

Step 1. (±)-(3S,4S)-benzyl4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate

(3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate (23 mg,0.073 mmol), 4-nitrophenyl chloroformate (16 mg, 1.1 equiv) and powderedNaHCO₃ (13 mg, 2 equiv) were mixed with acetonitrile (3 mL). The mixturewas stirred 1 h at rt. LC-MS showed the reaction was complete. Thereaction mixture was concentrated to afford (3S,4S)-benzyl4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylatewhich was used directly in the next step. LC-MS (3 min) t_(R)=2.24 min.,m/z 482 (M+1).

Step 2. (3SR,4SR)-benzyl3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate

Half of the crude (3S,4S)-benzyl4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylatefrom Step 1 was added to a solution of(S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol(29 mg, 2 equiv) and DIEA (15 μL, 3 equiv) in CH₂Cl₂ (2 mL). The mixturewas stirred for 1 h at rt. LC-MS showed the reaction was complete. Themixture was concentrated and purified by preparative HPLC to afford(3S,4S)-benzyl3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate(18.4 mg, 63%). LC-MS (3 min) t_(R)=2.40 min., m/z 672 (M+1).

Step 3.(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3RS,4RS)-4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide

(3S,4S)-benzyl3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate(18.4 mg, 0.027 mmol) and palladium(II) chloride (catalytic amount, c.a.4 mg) were mixed with EtOAc (3 mL). The flask was evacuated and filledby H₂ gas (3×). A balloon filled with H₂ gas was attached to the flaskto maintain the H₂ gas atmosphere for 2 h. LC-MS showed most of thestarting material had been converted to product. The mixture wasconcentrated, redissolved in acetonitrile (3 mL), filtered and purifiedby preparative HPLC to afford(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3RS,4RS)-4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide(16.6 mg, quant). LC-MS (3 min) t_(R)=1.58 min., m/z 538 (M+1).

Example 158

The following compounds were prepared using procedures analogous tothose described in Example 157:

-   (3R)—N-((3RS,4RS)-4-cyclohexylpiperidin-3-yl)-3-((S)-1-(2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide    (I-533A) using    (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    in Step 2.-   (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3RS,4RS)-4-(pentan-3-yloxy)piperidin-3-yl)piperidine-1-carboxamide    (I-549A) using (±)-(3R,4R)-benzyl    3-amino-4-(pentan-3-yloxy)piperidine-1-carboxylate in Step 1.

Example 159 (1S,2R)-2-amino-3-azido-1-(3-noradamantyl)propan-1-ol

Step 1. (2R,3S)-methyl 3-(3-noradamantyl)-2,3-dihydroxypropanoate

A 250-mL flask containing 180 mL of 1:1 ^(t)BuOH/H₂O (180 mL) at 0° C.was charged with the following reagents: (E)-methyl3-(3-noradamantyl)acrylate (4.1 g, 19.87 mmol), (DHQ)₂PHAL (155 mg,0.1987 mmol, 1 mol %), K₂Os(OH)₄ (36 mg, 0.0994 mmol, 0.5 mol %),K₃Fe(CN)₆ (19.63 g, 59.6 mmol, 3.0 equiv), MeSO₂NH₂ (1.89 g, 19.87 mmol,1.0 equiv), K₂CO₃ (8.24 g, 59.6 mmol, 3.0 equiv) and NaHCO₃ (5.12 g,59.6 mmol, 3.0 equiv). The mixture was placed in a refrigerator andallowed to stir for 3 d at 5° C. After this time Na₂S₂O₅ (15.8 g, 83.4mmol, 4.0 equiv) was added to the yellow slurry and the mixture stirredfor 1 h. The contents were transferred to a separatory funnel and thelayers were separated. The aqueous layer was extracted with EtOAc (4×30mL). The combined organic layers were washed with 1.0 M aq NaOH andbrine, dried over Na₂SO₄, filtered, and evaporated to afford anoff-white solid (7.15 g). Flash chromatography on silica, eluting with0-47% EtOAc in hexanes afforded (2R,35)-methyl3-(3-noradamantyl)-2,3-dihydroxypropanoate (3.4 g, 71%). The ee of theproduct was not determined.

Step 2a-c. (2S,3S)-methyl 2-azido-3-(3-noradamantyl)-3-hydroxypropanoate

A flask was charged with (2R,3S)-methyl3-(3-noradamantyl)-2,3-dihydroxypropanoate (3.4 g, 14.1 mmol, 1.0equiv), pyridine (4.5 mL, 56.4 mmol, 4.0 equiv) and CH₂Cl₂ (30 mL) andthe resulting solution was cooled to 0° C. Thionyl chloride (2.5 g, 21.2mmol, 1.5 equiv) was added via syringe and the mixture was stirred at 0°C. The reaction was monitored by LC-MS till the starting material wasconsumed. The mixture was diluted with water and additional CH₂Cl₂ andtransferred to a separatory funnel. The layers were separated andaqueous layer was extracted with additional CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andevaporated. The crude cyclic sulfite was used directly in the next step.

The cyclic sulfite was dissolved in 1:1 CCl₄/CH₃CN (20 mL). A solutionof NaIO₄ (4.5 g, 21.2 mmol, 1.5 equiv) of in H₂O (30 mL), and RuCl₃.xH2O(˜50 mg) were added and the resulting biphasic mixture was stirredrapidly overnight. Monitoring by LC-MS showed formation of the desiredcyclic sulfate. The mixture was diluted with EtOAc and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with satd aq NaHCO₃ and brine, andevaporated. The crude cyclic sulfate was dissolved in 5:1 acetone/water(100 mL). Solid NaN₃ (1.84 g, 28.2.5 mmol, 3.0 equiv) was added and themixture was stirred rapidly for 72 h. Analysis by LC-MS showedconsumption of the cyclic sulfate. The mixture was concentrated to avolume of ˜10 mL. To the residual solution was added 1:1 2.0NH₂SO₄/Et₂O(200 mL) and the mixture was stirred at rt for 18 h. The mixture wasdiluted with additional Et₂O/H₂O and the layers were separated. Theaqueous phase was extracted with additional Et₂O. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered, andevaporated. Flash chromatography on silica gel, eluting with 0-47% EtOAcin hexanes afforded (2S,3S)-methyl2-azido-3-(3-noradamantyl)-3-hydroxypropanoate (2.0 g, 7.7 mmol, 55%).

Steps 3a-d. tert-butyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-hydroxypropan-2-ylcarbamate

A 250-mL pressure bottle was charged with (2S,3S)-methyl2-azido-3-(3-noradamantyl)-3-hydroxypropanoate (2.0 g, 7.7 mmol), Boc₂O(1.7 g, 7.7 mmol), 10% Pd/C (˜100 mg) and MeOH (30 mL). The bottle wasfitted to a Parr hydrogenation shaker, pressurized to 45 psi with H₂,evacuated and backfilled with H₂ (3×). The reaction mixture was shakenunder 45 psi of H₂ for 18 h. LC-MS analysis showed no remaining azide.The mixture was filtered through a pad of Celite. The spent catalyst waswashed with additional methanol and the combined filtrates wereevaporated to dryness. The residue It was purified by flashchromatography on silica, eluting with 0-49% EtOAc in hexanes. Thisafforded (2S,3S)-methyl2-(tert-butoxycarbonylamino)-3-(3-noradamantyl)-3-hydroxypropanoate (1.6g, 61% yield).

(2S,3S)-methyl2-(tert-butoxycarbonylamino)-3-(3-noradamantyl)-3-hydroxypropanoate (1.6g, 4.7 mmol, 1.0 equiv) was dissolved in THF (40 mL) and the mixture wascooled to 0° C. LiBH₄ (2.0 M in THF, 4.7 mL, 9.4 mmol, 2.0 equiv) wasadded via syringe and the mixture was stirred overnight with concomitantwarming to ambient temperature. LC-MS analysis showed consumption of thestarting ester. The solution was cooled to 0° C. and excess LiBH₄ wasquenched with satd aq NH₄Cl. The mixture was diluted with water and thelayers were separated. The aqueous phase was extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and evaporated to afford tert-butyl(1S,2R)-1-(3-noradamantyl)-1,3-dihydroxypropan-2-ylcarbamate ofsufficient purity for use in the next step.

tert-Butyl (1S,2R)-1-(3-noradamantyl)-1,3-dihydroxypropan-2-ylcarbamate(852 mg, 2.74 mmol), 2,4,6-triisopropylphenylsulfonylchloride (2.48 g,8.21 mmol, 3.0 equiv), DABCO (922 mg, 8.21 mmol, 3.0 equiv) and DMAP(334 mg, 2.74 mmol, 1.0 equiv) were dissolved in CH₂Cl₂ and the mixturewas heated at reflux overnight. After this time tlc analysis showed ca50% conversion to the desired sulfonate ester. The mixture was dilutedwith CH₂Cl₂ and 0.5 M aq HCl. The layers were separated and the aqueouslayer was extracted with additional CH₂Cl₂. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered, andevaporated. The residue was purified by flash chromatography on silica,eluting with 0-19% EtOAc in hexanes to afford(2R,3S)-2-(tert-butoxycarbonylamino)-3-(3-noradamantyl)-3-hydroxypropyl2,4,5-triisopropylbenzenesulfonate (905 mg). Unreacted starting diol wasrecovered by eluting the column with EtOAc.

The sulfonate ester (70 mg, 0.133 mmol, 1.0 equiv) and NaN₃ (70 mg, 1.1mmol, 8.0 equiv) were dissolved in 3 mL of DMF and the mixture washeated to 70° C. for 18 h. Volatile materials were removed in vacuo andthe residue was dissolved in EtOAc, washed with brine, dried overNa₂SO₄, filtered, and evaporated. Flash chromatography on silica,eluting with 0-41% EtOAc in hexanes gave tert-butyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-hydroxypropan-2-ylcarbamate.

Step 4. (1S,2R)-2-amino-3-azido-1-(3-noradamantyl)propan-1-ol

tert-butyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-hydroxypropan-2-ylcarbamate (134mg, 0.399 mmol, 1.0 equiv) was dissolved in CH₂Cl₂. Hydrogen chloridesolution (4.0 M in dioxane, 4 mL, 40 equiv) was added and the mixturewas stirred at ambient temperature till the none of the startingmaterial was detected by LC-MS. The solvents were removed to afford(1S,2R)-2-amino-3-azido-1-(3-noradamantyl)propan-1-ol as its HCl saltwhich was used directly in the next step.

Example 160

The following compounds were prepared using procedures analogous tothose described in Example 159:

-   (1S,2R)-2-amino-3-azido-1-(trans-4-fluorocyclohexyl)propan-1-ol    using (E)-methyl 3-(trans-4-fluorocyclohexyl)acrylate in Step 1.

Example 161(3R)—N-((1S,2R)-3-amino-1-(3-noradamantyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide(I-493A)

Step 1. 4-nitrophenyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-(trimethylsilyloxy)propan-2-ylcarbamate

(1S,2R)-2-amino-3-azido-1-(3-noradamantyl)propan-1-ol HCl salt wasdissolved in CH₂Cl₂ (5 mL) and cooled to 0° C. Et₃N (0.5 mL) was added,followed by TMSCl (173 mg, 1.6 mmol, 4.0 equiv). After stirring for 3 h,LC-MS analysis showed complete conversion to the desired silyl ether.The volatile materials were removed in vacuo and the residue wasdissolved in CH₂Cl₂ (4.0 mL). This solution was treated with pyridine(0.35 mL) and p-NO₂C₆H₄OCOCl (120 mg, 0.599 mmol, 1.5 equiv). Themixture was stirred for 3 h. After this time LC-MS analysis showedformation of the desired 4-nitrophenyl carbamate. This solution of4-nitrophenyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-(trimethylsilyloxy)propan-2-ylcarbamatewas employed directly in the subsequent steps.

Step 2.(3R)—N-((1S,2R)-3-amino-1-(3-noradamantyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide

A solution of the 4-nitrophenyl(1S,2R)-3-azido-1-(3-noradamantyl)-1-(trimethylsilyloxy)propan-2-ylcarbamate(0.092 M in CH₂Cl₂, 0.5 mL, 0.46 mmol, 1.0 equiv) was treated with(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (16mg, 0.051 mmol, 1.1 equiv) and DIPEA (0.3 mL). The solution was allowedto stir for 16 h. After this time LC/MS analysis showed consumption ofthe starting carbamate. The solution was evaporated, dissolved in EtOAc,and washed with 1.0 Maq NaOH (3×3 mL), 1.0 M aq HCl (3 mL) and brine.The organic layer was evaporated and dissolved in 6:1 THF/H₂O (3.5 mL).A solution of PMe₃ (1.0 M in THF, 3.0 mL, 3.0 mmol, 6 equiv) was addedand the mixture heated to 50° C. under nitrogen. The solvent was removedand the residue was purified by prep HPLC to afford(3R)—N-((1S,2R)-3-amino-1-(3-noradamantyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide.The product was shown to have an optical purity of 50% ee.

Example 162

The following compounds were prepared using procedures analogous tothose described in Example 161:

-   (3R)—N-((1S,2R)-(3-amino-1-(3-noradamantyl)-1-hydroxy)propan-2-yl)-3-((S)-1-(2-fluoro-3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide    (I-499A) using    (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    in Step 2.-   (3R)—N-((1S,2R)-3-amino-1-(trans-4-fluorocyclohexyl)-1-hydroxypropan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide    (I-551A) using    (1S,2R)-2-amino-3-azido-1-(trans-4-fluorocyclohexyl)propan-1-ol in    Step 1 and    (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol    in Step 2.

Example 163 (S)-2-(trimethylsilyl)ethyl2-amino-3-cyclopentylpropyl(methyl)carbamate

Step 1a-c. 3-(3-noradamantyl)propanoic acid

A 250-mL flask was charged with 3-noradamantylcarboxaldehyde (3.3 g, 22mol), Ph₃PCHCO₂Me (9.2 g, 27.5 mmol, 1.25 equiv) and CHCl₃ (100 mL). Themixture was heated to reflux for 18 h. The clear solution was allowed tocool to ambient and evaporated. The sticky residue was taken up in 4:1hexanes/EtOAc (200 mL) and filtered through a pad of silica gel. The padwas washed with additional 4:1 hexanes/EtOAc (200 mL) and the filtratewas evaporated. The product was isolated by flash chromatography on 120g of silica, eluting with 0-17% EtOAc in hexanes. This afforded(E)-methyl 3-(3-noradamantyl)acrylate (4.13 g, 0.2 mmol, 90%).

A 500-mL pressure bottle was charged with (E)-methyl3-(3-noradamantyl)acrylate (7.8 g, 37.8 mmol), 10% Pd/C (1.8 g), and(MeOH) 100 mL. The bottle was fitted to a Parr hydrogenation shaker,pressurized to 50 psi with H₂, and evacuated. The fill/evacuationprocedure was repeated 3×, and the apparatus pressurized with 50 psi H₂and shoken for 3 h. After this time tlc analysis showed no remainingenoate. The mixture was filtered through a pad of celite. The spentcatalyst was washed with additional methanol and the combined filtrateswere evaporated to yield methyl 3-(3-noradamantyl)propanoate (7.8 g,37.8 mmol) in quantitative yield.

Methyl 3-(3-noradamantyl)propanoate (7.8 g, 37.8 mmol) was dissolved inTHF (150 mL) and the solution was cooled to 0° C. To this was added 1.0M aqueous LiOH (148 mL). The biphasic reaction mixture was vigorouslystirred at 0° C. After 3 h, a homogeneous solution was produced andLC-MS analysis showed no ester remained. The pH of the solution waslowered to ˜4 by the dropwise addition of concentrated HCl. The mixturewas transferred to a separatory funnel and the layers were separated.The aqueous layer was extracted with EtOAc (4×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and evaporated toafford 3-(3-noradamantyl)propanoic acid (7.15 g, 36.8 mmol) as a tackysolid.

Step 2. (S)-4-benzyl-3-(3-(3-noradamantyl)propanoyl)oxazolidin-2-one

3-(3-Noradamantyl)propanoic acid (7.15 g, 36.8 mmol, 1.0 equiv) wasdissolved in THF (70 mL) and the solution was cooled to 0° C. To thestirred solution were added N-methylmorpholine (4.25 mL, 38.7 mmol, 1.05equiv) and isobutyl chloroformate (4.52 mL, 38.7 mmol, 1.05 equiv). Awhite precipitate rapidly formed and the mixture containing the3-(noradamantyl)propanoic(isobutylcarbonic) anhydride was allowed tostir for 0.5 h at 0° C. A separate 500-mL 3-neck flask was charged withS-(−)-4-benzyloxazolidinone (8.5 g, 47.8 mmol, 1.35 equiv) and THF (100mL). The mixture was cooled to −78° C. and ^(n)BuLi (19.1 mL of a 2.5 Msolution) was added over a 10 min period. This was allowed to stir for0.5 h at −78° C. The first solution was rapidly filtered through a padof Celite and the resulting clear filtrate transferred via cannula tothe solution of the deprotonated oxazolidinone. After stirring for 0.5 hat −78° C. LC-MS analysis showed consumption of the mixed anhydride. Themixture was quenched with brine and allowed to warm to rt. The mixturewas transferred to a separatory funnel. The organic layer was separatedand evaporated. Flash chromatography (120 g SiO₂, 0-27% EtOAc inhexanes) afforded(S)-4-benzyl-3-(3-(3-noradamantyl)propanoyl)oxazolidin-2-one.

Step 3a-d. tert-butyl(S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-noradamantyl)-1-oxopropan-2-ylcarbamate

A solution of LDA was generated by charging an oven-dried 50-mL flaskwith dry THF (10 mL) and diisopropylamine (152 mg, 1.5 mmol, 1.5 equiv).The mixture was cooled to −0° C. and ^(n)BuLi (2.5 M, 0.6 mL, 1.5 mmol,1.5 equiv) added dropwise over 5 min. The mixture was stirred for 0.5 hand cooled to −78° C. A solution of(S)-4-benzyl-3-(3-(3-noradamantyl)propanoyl)oxazolidin-2-one (335 mg,1.0 mmol, 1.0 equiv) in THF (9 mL) was cooled to −78° C. and added tothe solution of LDA via cannula. The mixture was allowed to stir for 0.5h. A separate flask was charged with ^(t)BuCO₂N═NCO₂ ^(t)Bu (345 mg, 1.5mmol, 1.5 equiv) and THF (9 mL) and cooled to −78° C. This solution wastransferred to the enolate solution with the aid of a cannula. Theresulting mixture was allowed to stir at −78° C. for 0.5 h. Tlc analysisshowed consumption of the starting material. The mixture was quenchedwith HOAc (0.5 mL), and allowed to warm to rt. The solution wastransferred to a separatory funnel and the organic layer was washed withwater and brine, dried over Na₂SO₄ and filtered. The product waspurified by flash chromatography on SiO₂, eluting with 0-37% EtOAc inhexanes. This yielded di-tert-butyl1-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-noradamantyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylate(477 mg, 0.82 mmol, 82%).

The Boc protected hydrazine was dissolved in 3:1 CH₂Cl₂/TFA (20 mL) andstirred for 4 h. LC-MS analysis showed only the presence of the desiredproduct. The mixture was evaporated to afford(S)-4-benzyl-3-((S)-3-(3-noradamantyl)-2-hydrazinylpropanoyl)oxazolidin-2-oneas its TFA salt which was used directly in the next step.

The hydrazine TFA salt was dissolved in EtOH (10 mL) of and transferredto a Parr hydrogenation shaker. PtO₂ (56 mg, 0.25 mmol, 0.3 equiv) wasadded and the vessel pressurized to 60 psi with H₂, and evacuated. Thefill/evacuation procedure was repeated 3 times, and then the apparatuspressurized with 60 psi H₂ and shaken for 4 h. After this time thehydrazine was no longer observed in the LC/MS. The mixture was filteredand evaporated to give crude(S)-3-((S)-2-amino-3-cyclopentylpropanoyl)-4-benzyloxazolidin-2-onewhich was used without purification.

Crude(S)-3-((S)-2-amino-3-cyclopentylpropanoyl)-4-benzyloxazolidin-2-one fromthe previous step was dissolved in 1:1 acetonitrile/10% aqueous K₂CO₃(20 mL). Boc₂O (327 mg, 1.5 mmol, 1.8 equiv) was added and mixture wasstirred for 4 h. LC-MS showed consumption of the free amine. Theacetonitrile was removed in vacuo and the product was extracted withEtOAc (2×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and evaporated. Flash chromatography afforded tert-butyl(S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-noradamantyl)-1-oxopropan-2-ylcarbamate(148 mg, 0.32 mmol).

Step 4a-e. (S)-2-(trimethylsilyl)ethyl2-amino-3-(3-noradamantyl)propyl(methyl)carbamate

tert-butyl(S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-noradamantyl)-1-oxopropan-2-ylcarbamate(2.0 g, 4.23 mmol) was dissolved in THF and the solution was cooled to0° C. Methanol (250 μL) was added, followed by a solution of LiBH₄ (2.0M in THF, 8.6 mL, 4.0 equiv). The mixture was allowed to stir at 0° C.until LC-MS analysis indicated that the starting material had beenconsumed. Excess LiBH₄ was quenched by addition of satd aq NH₄Cl and thecontents were transferred to a separatory funnel. The layers wereseparated, the aqueous layer was extracted with EtOAc, and the combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated. The protected residue was purified by flash chromatographyon silica, eluting with 0-29% EtOAc in hexanes. This afforded(S)-tert-butyl 1-(3-noradamantyl)-3-hydroxypropan-2-ylcarbamate (1.24 g,>98%).

(S)-tert-butyl 1-(3-noradamantyl)-3-hydroxypropan-2-ylcarbamate (75 mg,0.25 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ and cooled to 0° C.Triethylamine (101 mg, 1.0 mmol, 4.0 equiv) was added, followed bymethanesulfonyl chloride (58 mg, 0.50 mmol, 2.0 equiv). The mixture wasallowed to stir till the starting material was consumed by LC.MSanalysis. The mixture was quenched by addition of satd aq NH₄Cl and thecontents were transferred to a separatory funnel. The layers wereseparated and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and evaporated to afford(S)-2-(tert-butoxycarbonylamino)-3-(3-noradamantyl)methanesulfonatewhich was used directly in the next step.

The crude mesylate was dissolved in of 33 wt % methylamine in ethanol(20 mL). The mixture was heated to reflux overnight. The solution wasevaporated and the residue was taken up in EtOAc. The solution waswashed with saturated NaHCO₃ and brine, and evaporated to afford crude(S)-tert-butyl 1-(3-noradamantyl)-3-(methylamino)propan-2-ylcarbamatewhich was used directly in the next step.

The crude amine was dissolved in 1:1 acetonitrile/10% aqueous K₂CO₃ (20mL). TeocOSu (97 mg, 0.375 mmol, 1.5 equiv) was added and mixture wasstirred for 4 h. LC-MS showed consumption of the free amine. Theacetonitrile was removed in vacuo and the aqueous residue was extractedwith EtOAc (2×20 mL). The combined organic extracts were dried overNa₂SO₄, filtered, and evaporated. The product was isolated by flashchromatography on silica eluting with 0-27% EtOAc.(S)-2-(trimethylsilyl)ethyl2-(t-butoxycarbonylamino)-3-(3-noradamantyl)propyl(methyl)carbamate (36mg, 0.080 mmol, 32% yield for Steps 4b-d) was isolated.

(S)-2-(trimethylsilyl)ethyl2-(t-butoxycarbonylamino)-3-(3-noradamantyl)propyl(methyl)carbamate (36mg, 0.080 mmol, 1.0 equiv) was dissolved in MeOH (5 mL). Toluenesulfonicacid hydrate (16 mg, 0.088 mmol, 1.1 equiv) was added and the solventwas removed at 65° C. under vacuum to afford (S)-2-(trimethylsilyl)ethyl2-amino-3-(3-noradamantyl)propyl(methyl)carbamate. This material wasused without purification.

Example 164(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(3-noradamantyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide(I-552A)

(S)-2-(trimethylsilyl)ethyl2-amino-3-(3-noradamantyl)propyl(methyl)carbamate was dissolved inacetonitrile (5 mL) and 10% aq Na₂CO₃ (1 mL) was added.Isopropenylchloroformate (17 μL, 0.159 mmol, 2.0 equiv) was added andthe solution was stirred for 1 h at rt. LC-MS analysis showed completeconversion to the desired isopropenyl carbamate. The acetonitrile wasremoved in vacuo and EtOAc was added. The mixture was transferred to aseparatory funnel and the layers were separated. The organic layer wasdried over Na₂SO₄, filtered, and evaporated. The crude(S)-2-(trimethylsilyl)ethyl2-(isopropenyloxycarbonylamino)-3-(3-noradamantyl)propyl(methyl)carbamatewas dissolved in acetonitrile and used in the subsequent step withoutfurther purification.

To the above isopropenyl carbamate solution (0.016 mmol, 1.0 equiv) wasadded a solution of(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (20mg, 0.064 mmol, 4.0 equiv) and DMAP (20 mg, 0.16 mmol, 10 equiv) inacetonitrile. The mixture was heated to 45° C. for 18 h. The solvent wasremoved and the residue was dissolved in EtOAc, washed with 0.5 M aq HCl(2×10 mL) and brine, and concentrated. The residue was dissolved inacetonitrile (2 mL) and transferred to a vial fitted for a microwavereactor. Et₄NF (ca 50 mg, 0.34 mmol, ˜20 equiv) was added. The vial wassealed, placed in the microwave reactor and heated to 119° C. for 7 min.LC-MS analysis showed formation of the desired amine. The solvent wasremoved and(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(3-noradamantyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamidewas isolated by prep HPLC.

Example 165 2-(trimethylsilyl)ethyl (R)-2-amino-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propyl(methyl)carbamate

Step 1a-dtert-butyl((1R,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilane

A 100-mL flask was charged with 7.2 g (50.7 mol) of the (1R,3s,5S)-ethyl6-oxabicyclo[3.1.0]hexane-3-carboxylate and NEt₃(HF)₃ (12.3 g, 76 mmol,1.5 equiv). The mixture was heated to 120° C. for 16 h. After this timetlc analysis showed consumption of the starting epoxide. The mixture wascooled to 0° C. and quenched by addition of satfd aq NaHCO₃. The mixturewas allowed to stir for 1 h, and diluted with EtOAc. The layers wereseparated and the aqueous layer extracted with additional EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄filtered, and evaporated. The residue was purified by flashchromatography on silica, eluting with 0-47% EtOAc in hexanes. Thisafforded (1S,3S,4S)-ethyl 3-fluoro-4-hydroxycyclopentanecarboxylate(6.73 g, 75% yield).

A solution of the (1S,3S,4S)-ethyl3-fluoro-4-hydroxycyclopentanecarboxylate (6.73 g, 38.2 mmol, 1.0equiv), TBSCl (11.5 g, 76.4 mmol, 2.0 equiv) and imidazole (12 g, 0.17mol, 4.0 equiv) in DMF (10 mL) was stirred at rt for 4 h. After thistime the free alchol was consumed by tlc analysis. The DMF was removedin vacuo and the residue was partitioned between ether and water. Thelayers were separated and the organic layer washed with brine, driedover Na₂SO₄ filtered, and evaporated. (1S,3S,4S)-ethyl3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentanecarboxylate wasisolated in quantitative yield.

A slurry of LiAlH₄ (2.99 g, 78.5 mmol, 2.0 equiv) in THF (100 mL) wascooled to −78° C. A solution of the above (1S,3S,4S)-ethyl3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentanecarboxylate in THF(50 mL) was added over 20 min, and the mixture was stirred at −78° C.for 0.5 h. Analysis by tlc showed consumption of the ester. The mixturewas allowed to warm to 0° C., then brine (10 mL) was added dropwise overa 15 min, followed by ˜20 g of Celite. The thick slurry was diluted withEtOAc and allowed to stir for 0.5 h. The mixture was filtered through apad of Celite. The filter cake was washed with additional EtOAc. Theresulting clear solution was dried over Na₂SO₄, filtered, andevaporated. This afforded((1S,3S,4S)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methanol7.24 g (76% yield).

The above alcohol (7.24 g, 29.1 mmol, 1.0 equiv), triphenylphosphine(9.2 g (35 mmol, 1.2 equiv), and imidazole (4.0 g, 58.3 mmol, 2.0 equiv)were dissolved in THF (100 mL) and cooled to 0° C. Iodine (8.15 g, 32.4mmol, 1.1 equiv) was added in 3 equal portions over a 20 min. Themixture was stirred for 1 h at 0° C. After this time additionaltriphenylphosphine (0.125 equiv) was added, followed by additionaliodine (0.125 equiv). After stirring for 20 min tlc analysis showed noremaining alcohol. The mixture was filtered through a pad of silica. Thesilica was washed with ether and the filtrate was evaporated.tert-butyl((1R,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilanewas isolated by flash chromatography on silica, eluting with 0-9% EtOAcin hexanes.

Step 2a-b. (S)-methyl2-(benzyloxycarbonylamino)-3-((1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)propanoate

An oven-dried 250-mL flask was charged with dry THF (75 mL) and(R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (4.02 g, 21.8 mmol,1.5 equiv). The mixture was cooled to −78° C. (dry ice/IPA) and ^(n)BuLi(2.5 M, 8.72 mL, 21.8 mmol, 1.5 equiv) was added dropwise over a 20 min.After addition was complete the flask was maintained at −78° C. for 1 h.After this time a solution oftert-butyl((1R,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilane(5.2 g, 14.5 mmol, 1.0 equiv) in THF (25 mL) was added over 10 min. Themixture was stirred at −78° C. for 2 h, then tightly stoppered and thedry ice/IPA bath placed in a −15 C freezer for 19 h. After this timeLC-MS analysis showed consumption of the iodide and formation of thedesired product (M+H⁺). The reaction was quenched by addition of satd aqNH₄Cl (10 mL) and the THF removed in vacuo. The residue was partitionedbetween EtOAc and H₂O. The water layer was extracted with additionalEtOAc and the combined organic layers washed with brine, dried overdried over Na₂SO₄, filtered and evaporated. The desired(2S,5R)-2-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine,contaminated with the starting and(R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine, was used directly inthe next step.

The pyrazine mixture was dissolved in 1:1 acetonitrile/1.0 M aqueous HCl(200 mL). The mixture was stirred for 7 h at rt. The volatile componentswere removed in vacuo. The residue was dissolved in 1:1acetonitrile/water (100 mL). To this solution was added K₂CO₃ (15.2 g,0.110 mol, 5.0 equiv) and CbzOSu (10.9 g, 43.6 mmol, 3.0 equiv) and theresulting mixture allowed to stir for 17 h. After this time the volatilematerials were removed and the residue was partitioned between EtOAc andwater. The layers were separated and the organic layer was washed withsatd aq NaHCO₃ and brine, dried over Na₂SO₄ filtered, and evaporated.The crude amino acid derivative was purified by flash chromatography, onsilica, eluting with 0 to 47% EtOAc in hexanes. This afforded (S)-methyl2-(benzyloxycarbonylamino)-3-((1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)propanoate(4.4 g, 89% yield).

Step 3. (S)-methyl2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propanoate

(S)-methyl2-(benzyloxycarbonylamino)-3-((1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)propanoate(4.4 g, 12.9 mmol, 1.0 equiv) was dissolved in THF (50 mL) and cooled to0° C. To this solution was added C₄F₉SO₂F (7.86 g, 25.93 mmol, 2.0equiv), NEt₃(HF)₃ (4.18 g, 25.93 mmol, 2.0 equiv), and NEt₃ (7.84 g,77.8 mmol, 6.0 equiv). The resulting mixture was allowed to stir for 72h. After this time the solution was filtered through a pad of silica.The silica was washed with additional THF and the filtrate wastransferred to a separatory funnel. The solution was washed withsaturated NaHCO₃ and brine and evaporated. The desired vicinaldifluoride was purified by flash chromatography on silica. This afforded(S)-methyl2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propanoate(3.0 g). Unreacted starting alcohol (818 mg) was also recovered.

Step 4. 2-(trimethylsilyl)ethyl(R)-2-amino-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propyl(methyl)carbamate

LiAlH₄ (1.0 g, 26.5 mmol, 3.0 equiv) was slurried in THF (100 mL) andcooled to −78° C. A solution of (S)-methyl2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propanoate(3.0 g, 8.84 mmol) in THF (20 mL) was added over 20 min. After this timeLC-MS analysis showed no remaining starting material. The mixture waswarmed to 0° C. and brine (7 mL) was added dropwise, followed by ca 10 gof Celite. The thick slurry was stirred for 0.5 h, and filtered througha pad of Celite. The clear solution was evaporated to yield benzyl(S)-1-((1r,3R,4S)-3,4-difluorocyclopentyl)-3-hydroxypropan-2-ylcarbamateas a thick syrup (1.8 g, 65% yield).

A 250-mL flask was charged with the above alcohol (1.8 g, 5.75 mmol),brosyl chloride (2.94 g, 11.5 mmol, 2.0 equiv), DMAP (351 mg, 2.87 mmol,0.5 equiv) and 5:1 CH₂Cl₂:pyridine (120 mL). The mixture was allowed tostir for 17 h at rt. After this time the volatile materials were removedin vacuo and the residue was partitioned between EtOAc and 1.0 M aq HCl.The layers were separated, and the organic layer evaporated.(S)-2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propyl4-bromobenzenesulfonate was purified by flash chromatography on silicagel, eluting with 0-80% EtOAc in hexanes.

The above brosylate was dissolved in 30% NH₂Me in EtOH (100 mL). Themixture was heated at reflux for 15 h. After this time the solvent wasremoved and the residue was dissolved in fresh 30% NH₂Me in EtOH (100mL), and the mixture was heated to reflux for an additional 8 h. Afterthis time the volatile materials were removed and the residue wasdissolved in 1:1 CH₃CN:10% aqueous K₂CO₃ (40 mL). TeocOSu (2.22 g, 8.83mmol, 1.5 equiv) was added and mixture stirred for 4 h. LC-MS showedconsumption of the free amine. The acetonitrile was removed in vacuo andthe product was extracted with EtOAc (2×20 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and evaporated.2-(trimethylsilyl)ethyl(S)-2-(benzyloxycarbonylamino)-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propyl(methyl)carbamatewas isolated by flash chromatography on silica gel eluting with 0-7%MeOH in CH₂Cl₂.

A crude sample of the above diamine dissolved in MeOH (10 mL) was addedto a 250-mL Parr pressure bottle containing 10% Pd (ca 100 mg) on carbonand MeOH (7 mL). The bottle was placed in a hydrogenation shaker andpressurized to 45 psi of H₂, then evaporated. This procedure wasrepeated twice, the mixture was placed in the shaker for 3 h. After thistime the Cbz group was cleanly removed. The catalyst was removed byfiltration through Celite and the volatile materials removed to afford2-(trimethylsilyl)ethyl(R)-2-amino-3-((1r,3R,4S)-3,4-difluorocyclopentyl)propyl(methyl)carbamate(109 mg) as a clear oil. This amine was of sufficient purity to employin subsequent steps.

Example 166

The following compounds were prepared using procedures analogous tothose described in Example 165:

-   2-(trimethylsilyl)ethyl    (2S)-2-amino-3-(tetrahydro-2H-pyran-2-yl)propylcarbamate using    2-(iodomethyl)tetrahydro-2H-pyran in step 2.-   2-(trimethylsilyl)ethyl    (2S)-2-amino-3-(tetrahydrofuran-2-yl)propylcarbamate using    2-(iodomethyl)tetrahydrofuran in step 2.-   (S)-2-(trimethylsilyl)ethyl    2-amino-3-(3-methoxycyclobutyl)propylcarbamate using    1-(iodomethyl)-3-methoxycyclobutane in step 2.

The following are compounds of the invention. Compound names weregenerated with the assistance of ChemDraw® versions 8.0 and 9.0(CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, Mass.02140 USA). When the stereochemistry at a chiral center is not definedin the compound name this indicates that the sample prepared contained amixture of isomers at this center.

Table of Compounds Method of LC-MS Cpd. Synthesis (3 min) tR Mass No.Cpd. Name Example No. (min) observed Selected 1H NMR^(a) I-1AN-((S)-1-amino-3-cyclohexylpropan- 33 1.57 430 7.26-7.05 (m), 4.29-3.70(m), 2-yl)-3-(1-hydroxy-1-phenylpentyl)- 2.89-2.21 (m), 1.83-0.69 (m)piperidine-1-carboxamide I-2A 3-((3- 42 1.55 439 8.29 (m), 7.82-7.10(m), 5.36-5.32 (m), methoxypropoxy)(phenyl)methyl)- 4.33 (m), 3.46-2.82(m), 1.83-0.76 (m) N-((S)-1-amino-3-cyclohexylpropan-2- yl)benzamideI-3A 3-((2- 33 1.72 442 7.13-7.27 (m), 4.17-4.33 (m),cyclopropylethoxy)(phenyl)methyl)- 3.69-4.05 (m), 2.54-2.92 (m),0.61-1.71 (m), N-((S)-1-amino-3-cyclohexylpropan- 0.25-0.31 (m),−0.15-−0.09 (m) 2-yl)piperidine-1-carboxamide I-4AN-((S)-1-amino-3-cyclohexylpropan- 33 1.68 444 7.26-6.99 (m), 3.95-3.46(m), 3.11 (m), 2-yl)-3-(5-methoxy-1- 2.89-1.94 (m), 1.70-0.71 (m)phenylpentyl)piperidine-1- carboxamide I-5A 3-((3- 33 1.53 446 7.24-7.12(m), 4.27-4.15 (m), methoxypropoxy)(phenyl)methyl)- 3.99-3.55 (m),3.38-3.10 (m), 2.90-2.42 (m), N-((S)-1-amino-3-cyclohexylpropan-2-1.86-0.71 (m) yl)piperidine-1-carboxamide I-5B (3S)-3-((3- 33 1.53 4467.38-7.33 (m, 2H), 7.32-7.26 (m, 3H), methoxypropoxy)(phenyl)methyl)-4.09 (d, 1H), 3.98 (m, 1H), 3.70 (dd, 1H),N-((S)-1-amino-3-cyclohexylpropan-2- 3.50-3.43 (m, 2H), 3.36 (m, 1H),2.97 (dd, yl)piperidine-1-carboxamide 1H), 2.78-2.64 (m, 3H), 2.00 (dm,1H) I-5C (3R)-3-((R)-(3- 33 1.55 446 7.37-7.32 (m, 2H), 7.32-7.25 (m,3H), methoxypropoxy)(phenyl)methyl)- 4.32 (d, 1H), 4.04 (m, 1H),4.00-3.88 (m, N-((S)-1-amino-3-cyclohexylpropan-2- 2H), 3.51-3.39 (m,2H), 3.02 (dd, 1H), yl)piperidine-1-carboxamide 2.86-2.74 (m, 3H)I-6A^(b) 3-((3- 127 1.44 446 0.80-1.80 (m)2.10 (m), 3.20 (s), 4.10 (m)methoxypropoxy)(phenyl)methyl)-N- 7.10-7.50 (m) (2-amino-3-cyclohexylpropyl)piperidine-1- carboxamide I-7A^(b) (3R)-N-(1-amino-3-45 1.43 446 3.70-3.90 (m), 4.20 (m), 7.10-7.40 (m)cyclopentylpropan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-8A^(c) 2-((3- 33 1.41 448 1.80(m), 2.79 (m), 2.99 (m), 3.30 (s), methoxypropoxy)(phenyl)methyl)- 3.78(br t), 4.07 (m), 4.22 (m) N-((S)-1-amino-3-cyclohexylpropan-2-yl)morpholine-4-carboxamide I-9A^(b) (3R)-N-((R)-3-tert-butoxy-1- 451.32 450 1.15 (s), 3.25 (s), 3.75 (m), 4.20 (m),aminopropan-2-yl)-3-((S)-1- 7.10-7.25 (m) hydroxy-5-methoxy-1-phenylpentyl)piperidine-1- carboxamide I-10A(3R)-3-((S)-1-(3-fluorophenyl)-1- 30 1.37 452 0.92 (d), 0.98 (d),1.2-2.0 (m), 2.54 (m), hydroxy-5-methoxypentyl)-N-((S)-4- 2.70 (s), 2.96(m), 3.06 (m), 3.24 (s), methyl-1-(methylamino)pentan-2- 3.3 (m), 3.96(d), 4.08 (m), 4.32 (d), 6.94 (m), yl)piperidine-1-carboxamide 7.16 (m),7.32 (m) I-11A 3-((3- 42 1.57 453 7.77-7.06 (m), 5.30 (s), 4.37 (m),methoxypropoxy)(phenyl)methyl)- 3.40-3.35 (m), 3.14 (s), 3.04-2.91 (m),2.56 (s), N-((S)-3-cyclohexyl-1- 1.77-0.74 (m) (methylamino)propan-2-yl)benzamide I-12A^(b) (3R)-N-((S)-1-amino-3- 44 1.32 454 2.50-2.80 (m),2.60-2.90 (m), 3.30 (s), phenylpropan-2-yl)-3-((S)-1- 4.10 (m),7.10-7.40 (m) hydroxy-5-methoxy-1- phenylpentyl)piperidine-1-carboxamide I-13A N-((S)-1-amino-3-cyclohexylpropan- 33 1.79 4587.28-7.08 (m), 4.32-3.72 (m), 2-yl)-3-(1-hydroxy-1- 2.91-2.24 (m),1.90-0.73 (m) phenylheptyl)piperidine-1- carboxamide I-14AN-((S)-1-amino-3-cyclohexylpropan- 36 1.64 458 not determined2-yl)-3-(5-ethoxy-1- phenylpentyl)piperidine-1- carboxamide I-14AN-((S)-3-cyclohexyl-1- 37 1.7 458 not determined(methylamino)propan-2-yl)-3-(5- methoxy-1-phenylpentyl)piperidine-1-carboxamide I-15A (3S)-N-((S)-3-cyclohexyl-1- 37 1.76 458 notdetermined (methylamino)propan-2-yl)-3-((R)-5-methoxy-1-phenylpentyl)piperidine- 1-carboxamide I-16A^(b) 3-((3- 302.77 460 2.65 (s), 2.95 (m), 3.35 (s), 4.17 (m),methoxypropoxy)(phenyl)methyl)-N- 7.10-7.50 (m) (3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-17A 3-((4- 33 1.61460, 7.34-7.24 (m, 5H), 4.29 (d, 1H), methoxybutoxy)(phenyl)methyl)- 4824.02 (m, 1H), 3.92 (m, 1H), 3.51-3.38 (m,N-((S)-1-amino-3-cyclohexylpropan-2- 4H), 2.99 (dd, 1H), 2.82-2.73 (m,2H) yl)piperidine-1-carboxamide I-17A 3-((3- 33 1.63 460 3.28 (m), 4.28(d), 4.38 (d), 7.24-7.38 (m) ethoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-18AN-((S)-1-amino-3-cyclohexylpropan- 33 1.6 460 3.27 (m), 3.70 (m), 3.81(m), 3.95 (m), 2-yl)-3-(1-hydroxy-5-methoxy-1- 4.02 (m), 4.10 (m), 4.29(d), 4.39 (d), phenylpentyl)piperidine-1- 7.25-7.36 (m) carboxamideI-19A (3R)-N-((S)-1-amino-3- 33 1.48 460 7.24-7.00 (m, 5H), 4.12 (dm, J= 12.8 Hz, cyclohexylpropan-2-yl)-3-((S)-1- 1H), 3.93-3.86 (m, 1H), 3.79(dm, J = 12.8 Hz, hydroxy-5-methoxy-1- 1H), 3.14-3.11 (m, 2H), 3.07 (s,phenylpentyl)piperidine-1- 3H), 2.84 (dd, J = 12.6, 3.4 Hz, 1H),carboxamide 2.68 (dd, J = 12.6, 9.8 Hz, 1H), 2.33 (t, J = 12.2 Hz, 2H),1.84-0.66 (m, 25H) I-19A 3-((3- 33 1.47 460 7.25-7.05 (m), 4.29-3.70(m), 3.12 (m), methoxypropoxy)(phenyl)methyl)-N- 2.89-2.21 (m),1.86-0.72 (m) (1-amino-3-cyclohexylpropan-2-yl)-N-methylpiperidine-1-carboxamide I-20A (3R)-N-((S)-3-cyclohexyl-1- 301.58 460 2.70 (s), 3.30 (s), 3.90 (br m),(methylamino)propan-2-yl)-3-((R)-1- 7.20-7.50 (m) hydroxy-4-methoxy-1-phenylbutyl)piperidine-1- carboxamide I-21A (3R)-3-((R)-(3- 33 1.59 4600.85-1.08 (m), 2.00 (m), 2.65 (s), 2.69 (s),ethoxypropoxy)(phenyl)methyl)- 3.04 (d), 3.07 (d), 3.25 (s), 3.26 (s),N-((S)-1-amino-3-cyclohexylpropan-2- 3.29-3.34 (m), 3.98 (m), 4.13 (m),4.28 (d), yl)piperidine-1-carboxamide 7.19-7.42 (m) I-22A3-((3-methoxypropoxy)(4- 33 1.59 464 0.8-2.0 (m), 3.30 (s), 7.08 (t),7.28 (t) fluorophenyl)methyl)-N-((S)-1- amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-23A 3-((3-methoxypropoxy)(2- 33 1.59 4640.8-1.9 (m), 3.28 (s), 4.0 (m), 7.04 (t), fluorophenyl)methyl)-N-((S)-1-7.20 (t), 7.35 (m), 7.41 (m) amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-24A (3S)-N-((S)-3-cyclohexyl-1- 38 1.89464 4.03-3.98 (m, 1H), 3.91 (dm, J = 12.8 Hz,(methylamino)propan-2-yl)-3-((S)-1- 1H), 3.82 (dm, J = 12.8 Hz, 1H),3.28 (t, J = 6.6 Hz, cyclohexyl-5- 2H), 3.20 (s, 3H), 2.93 (dd, J =12.4, methoxypentyl)piperidine-1- 3.2 Hz, 1H), 2.80 (dd, J = 12.4, 10.0Hz, carboxamide 1H), 2.58 (s, 3H), 2.61-2.48 (m, 2H), 1.70-0.72 (m, 37H)I-24B (3S)-N-((S)-3-cyclohexyl-1- 38 1.98 464 4.05-3.99 (m, 1H), 3.93(dm, J = 12.8 Hz, (methylamino)propan-2-yl)-3-((R)-1- 1H), 3.84 (dm, J =13.0 Hz, 1H), 3.31 (t, J = 6.4 Hz, cyclohexyl-5- 2H), 3.23 (s, 3H), 2.96(dd, J = 12.6, methoxypentyl)piperidine-1- 3.4 Hz, 1H), 2.80 (dd, J =12.6, 10.2 Hz, carboxamide 1H), 2.60 (s, 3H), 2.64-2.51 (m, 2H),1.71-0.74 (m, 37H) I-25A (3R)-N-((S)-3-cyclohexyl-1- 33 1.71 470(methylamino)propan-2-yl)-3-(4- cyclopropyl-1-hydroxy-1-phenylbutyl)piperidine-1- carboxamide I-26A 3-((3-methoxypropoxy)(3- 301.84 514 3.30 (m), 4.12 (m), 7.34 (m) cyanophenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-27AN-((S)-3-cyclohexyl-1- 37 1.78 472 7.14-6.93 (m), 3.97-3.45 (m),(methylamino)propan-2-yl)-3-(5- 3.24-3.11 (m), 2.89-2.59 (m), 2.51 (s),2.46 (s), ethoxy-1-phenylpentyl)piperidine-1- 2.28-2.18 (m), 1.92-1.89(m), carboxamide 1.75-0.65 (m) I-28A^(d) N-((S)-3-cyclohexyl-1- 40 1.45473 2.62 (s), 2.74 (s), 2.76 (s) 3.90 (m),(methylamino)propan-2-yl)-3-(1- 3.26 (s), 7.18 (m), 7.27 (m), 7.38 (m)hydroxy-5-methoxy-1- phenylpentyl)cyclohexanecarboxamide I-29A^(b)N-(1-amino-4- 45 1.37 474 1.15 (m), 2.60 (m), 3.80 (m), 3.25 (s),(trifluoromethyl)pentan-2-yl)-3-(1- 4.10 (m), 7.10-7.25 (m)hydroxy-5-methoxy-1- phenylpentyl)piperidine-1- carboxamide I-30^(b)3-((3- 30 1.6 474 0.95 (m), 2.9 (m), 3.80 (m), 4.1 (m)methoxypropoxy)(phenyl)methyl)-N- 7.20-7.50 (m)(3-cyclohexyl-1-(ethylamino)propan- 2-yl)piperidine-1-carboxamide I-31A3-((3- 33 1.67 474 ethoxypropoxy)(phenyl)methyl)- N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-31B (3R)-3-((R)-(3-32 1.58 474 7.34 (m, 2H), 7.27 (m, 3H), 4.30 (d, 1H),ethoxypropoxy)(phenyl)methyl)- 4.10 (m, 1H), 3.94 (m, 2H), 3.52-3.40 (m,N-((S)-3-cyclohexyl-1- 4H), 3.01-2.87 (m, 2H), 2.76 (td, 2H),(methylamino)propan-2- 2.65 (s, 3H) yl)piperidine-1-carboxamide I-32A(3R)-N-((S)-1-amino-3- 33 1.56 474 7.30-7.09 (m, 5H), 4.19 (dm, J = 12.8Hz, cyclohexylpropan-2-yl)-3-((S)-5- 1H), 3.95 (m, 1H), 3.87 (dm, J =12.8 Hz, ethoxy-1-hydroxy-1- 1H), 3.34-3.19 (m, 4H), 2.93-2.87 (m,phenylpentyl)piperidine-1- 1H), 2.77-2.69 (m, 1H), 2.44-2.37 (m,carboxamide 2H), 1.90-0.78 (m, 28H) I-33A (3R)-N-((S)-3-cyclohexyl-1- 331.49 474 7.14-6.94 (m, 5H), 4.05 (dm, J = 12.8 Hz,(methylamino)propan-2-yl)-3-((S)-1- 1H), 3.93-3.87 (m, 1H), 3.73 (dm, J= 12.4 Hz, hydroxy-5-methoxy-1- 1H), 3.08-3.05 (m, 2H), 3.01 (s,phenylpentyl)piperidine-1- 3H), 2.82 (dd, J = 12.8, 3.2 Hz, 1H),carboxamide 2.71 (dd, J = 12.4, 10.0 Hz, 1H), 2.46 (s, 3H), 2.28 (t, J =12.2 Hz, 2H), 1.78-0.63 (m, 25H) I-34A 3-((3- 33 1.76 474 7.35-7.25 (m,5H), 4.05 (s, 2H), 3.89 (m, ethoxypropoxy)(phenyl)methyl)- 1H), 3.64 (d,1H), 3.52 (m, 2H), 3.45 (m, N-((S)-1-amino-3-cyclohexylpropan-2- 2H),3.37-3..18 (m, 3H), 3.50-2.90 (m, 2H), yl)-3-methylpiperidine-1- 2.81(1H) carboxamide I-35A (3R)-N-((S)-3-cyclohexyl-1- 33 1.65 475 2.02 (m),2.65 (s), 2.70 (s), 2.91 (m), (methylamino)propan-2-yl)-3-((R)-4- 3.04(d), 3.07 (d), 3.30 (m), 3.33-3.43 (m), ethoxy-1-hydroxy-1- 3.98 (d),4.13 (m), 4.29 (d), 7.19-7.43 (m) phenylbutyl)piperidine-1- carboxamideI-36A (3R)-N-((S)-2-amino-5-methoxy-4,4- 126.1 1.41 498 0.98 (s), 1.00(s), 1.20-1.80 (m), 1.94 (m), dimethylpentyl)-3-((S)-1-(3- 2.44 (dd),2.58 (dd), 3.16 (d), 3.22 (d), chlorophenyl)-1-hydroxy-5- 3.24 (s), 3.30(m), 3.38 (s), 3.88 (d), methoxypentyl)piperidine-1- 4.38 (d), 7.20-7.32(m), 7.42 (s). carboxamide I-37A (3S)-N-((S)-3-cyclohexyl-1- 37 1.68 4760.9-1.9 (m), 2.40 (m), 2.68 (s), 2.92 (dd),(methylamino)propan-2-yl)-3-((R)-1- 3.06 (m), 3.24 (s), 3.90 (d), 4.16(m), (3-fluorophenyl)-5- 6.88 (m), 6.92 (m), 7.28 (m)methoxypentyl)piperidine-1- carboxamide I-38A(3R)-N-((S)-3-cyclohexyl-1- 43 1.64 476 7.29-7.15 (m, 5H), 4.23 (dm, J =13.2 Hz, (methylamino)propan-2-yl)-3-(1- 1H), 4.05-3.92 (m, 1H), 3.86and fluoro-5-methoxy-1- 3.71 (dm, J = 13.2 Hz, 1H), 3.20-3.15 (m, 1H),phenylpentyl)piperidine-1- 3.13 (s, 3H), 3.00-2.73 (m, 2H), 2.59 andcarboxamide 2.55 (s, 3H), 2.51-2.39 (m, 2H), 2.08-0.74 (m, 25H) I-39A(3R)-3-((R)-(3-methoxypropoxy)(3- 33 478 2.73 (d, 3H), 3.31 (s, 1H),3.48 (m, 2H), fluorophenyl)methyl)-N-((S)-3- 3.56 (t, 1H), 3.77 (m, 1H),3.92 (br d, 1H), cyclohexyl-1-(methylamino)propan- 4.02 (brd, 1H), 4.12(m, 1H), 4.26 (br d, 2-yl)piperidine-1-carboxamide 1H), 7.03 (m, 2H),7.10 (d, 1H), 7.37 (m, 1H) I-40A (3R)-N-((S)-1-amino-3- 33 478 3.26 (s),3.84 (br d), 3.97 (br d), 4.05 (m), cyclohexylpropan-2-yl)-3-((S)-1-(3-4.29 (br d), 4.42 (br d), 6.93 (m), fluorophenyl)-1-hydroxy-5- 7.15 (m),7.34 (m) methoxypentyl)piperidine-1- carboxamide I-41A(3R)-N-((S)-3-cyclohexyl-1- 33 1.59 480 4.05-4.00 (m, 1H), 3.93 (dm, J =12.8 Hz, (methylamino)propan-2-yl)-3-((R)-1- 2H), 3.31 (t, J = 6.4 Hz,2H), 3.22 (s, 3H), cyclohexyl-1-hydroxy-5- 2.95 (dd, J = 12.4, 3.2 Hz,1H), 2.81 (dd, methoxypentyl)piperidine-1- J = 12.4, 10.2 Hz, 1H), 2.59(s, 3H), carboxamide 2.67-2.54 (m, 2H), 1.78-0.72 (m, 36H) I-41A(3R)-N-((S)-3-cyclohexyl-1- 33 1.6 480 4.07-4.01 (m, 1H), 3.94 (dm, J =12.8 Hz, (methylamino)propan-2-yl)-3-((S)-1- 2H), 3.32 (t, J = 6.4 Hz,2H), 3.22 (s, 3H), cyclohexyl-1-hydroxy-5- 2.96 (dd, J = 12.6, 3.4 Hz,1H), 2.80 (dd, methoxypentyl)piperidine-1- J = 12.8, 10.2 Hz, 1H), 2.59(s, 3H), carboxamide 2.67-2.54 (m, 2H), 1.79-0.73 (m, 36H) I-42A3-((3-methoxypropoxy)(2,4- 33 1.55 482 not determineddifluorophenyl)methyl)-N-((S)-1- amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-43A 3-((3-methoxypropoxy)(3,4- 33 1.59 4827.15-7.06 (m), 4.42-3.66 (m), difluorophenyl)methyl)-N-((S)-1- 3.40-3.11(m), 2.91-2.46 (m), 1.82-0.73 (m) amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide I-44A (3R)-3-((S)-1-hydroxy-5-methoxy-1- 331.40 484 1.18 (d), 2.60 (s), 3.22 (s), 3.82 (d),(2-phenoxyphenyl)pentyl)-N-((S)-1- 4.00 (m), 4.32 (d), 6.72 (d), 6.84(d), 7.04 (m), (methylamino)propan-2- 7.14 (m), 7.28 (m), 7.60 (d)yl)piperidine-1-carboxamide I-45A 3-((3-methoxypropoxy)(3- 30 1.5 4853.01 (m), 3.24 (m), 3.41 (m), 4.03 (m), cyanophenyl)methyl)-N-((S)-3-7.49-7.64 (m) cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-46A 3-((3-methoxypropoxy)(2- 33 1.75 4860.9-1.8 (m), 2.8 (m), 3.28 (s), 5.06 (m),allylphenyl)methyl)-N-((S)-1-amino- 5.98 (m), 7.20 (m), 7.35 (m)3-cyclohexylpropan-2-yl)piperidine- 1-carboxamide I-47A^(b) 3-((3- 301.69 488 0.95 (m), 1.75 (m), 2.9 (m), 3.80 (m),methoxypropoxy)(phenyl)methyl)-N- 4.1 (m) 7.20-7.50 (m) (3-cyclohexyl-1-(propylamino)propan-2- yl)piperidine-1-carboxamide I-48A(3R)-N-((S)-3-cyclohexyl-1- 33 1.59 488 7.22-7.02 (m, 5H), 4.13 (dm, J =12.8 Hz, (methylamino)propan-2-yl)-3-((S)-5- 1H), 4.01-3.94 (m, 1H),3.80 (dm, J = 12.8 Hz, ethoxy-1-hydroxy-1- 1H), 3.24 (q, J = 6.9 Hz,2H), phenylpentyl)piperidine-1- 3.18 (t, J = 6.6 Hz, 2H), 2.89 (dd, J =12.8, carboxamide 3.6 Hz, 1H), 2.78 (dd, J = 12.4, 10.0 Hz, 1H), 2.53(s, 3H), 2.35 (t, J = 12.2 Hz, 2H), 0.95 (t, J = 7.0 Hz, 3H), 1.87-0.68(m, 25H) I-49A 3-((3- 30 1.83 488 0.87 (m), 2.65 (s), 2.69 (s), 3.30(m), propoxypropoxy)(phenyl)methyl)- 3.30 (m), 3.74 (d), 4.10 (d), 4.30(d), 4.42 (d), N-((S)-3-cyclohexyl-1- 7.39-7.23 (m)(methylamino)propan-2- yl)piperidine-1-carboxamide I-50A(3R)-N-((S)-3-cyclohexyl-1- 33 488 2.34 (s), 2.71 (s), 2.72 (s), 3.07(dd), (methylamino)propan-2-yl)-3-((R)-1- 3.84 (br d), 3.98 (br d), 4.13(br d), 4.26 (br d), hydroxy-5-methoxy-1-m- 4.41 (br d)tolylpentyl)piperidine-1- carboxamide I-50B (3R)-N-((S)-3-cyclohexyl-1-33 488 (methylamino)propan-2-yl)-3-((S)-1- hydroxy-5-methoxy-1-m-tolylpentyl)piperidine-1- carboxamide I-51A(3R)-N-((S)-1-amino-5-methoxy-4,4- 33 1.41 498 0.96 (s), 0.98 (m),1.08-1.80 (m), dimethylpentan-2-yl)-3-((S)-1-(3- 1.96 (m), 2.46 (m),2.58 (m), 2.84 (m), chlorophenyl)-1-hydroxy-5- 2.98 (m), 3.08 (s), 3.24(s), 3.30 (m), 3.92 (d), methoxypentyl)piperidine-1- 4.08 (m), 4.36 (d),7.20-7.34 (m), carboxamide 7.42 (m). I-52A (2S)-N2-(1-(3-((3- 34 1.92589 7.41-7.23 (m, 5H), 4.40-4.00 (m, 3H),methoxypropoxy)(phenyl)methyl)piperidin- 3.73 (m, 1H)1-yl)-2-nitrovinyl)-3- cyclohexylpropane-1,2-diamine I-53A(3R)-N-((S)-3-cyclohexyl-1- 33 492 2.59 (s), 3.05 (dd), 3.29 (S), 3.84(brd), (methylamino)propan-2-yl)-3-((R)-1- 3.98 (br d) 4.13 (m),, 4.19(br d), 4.28 (br (3-fluorophenyl)-1-hydroxy-5- d), 4.45 (br d), 6.95 (m,1H), 7.15 (m, methoxypentyl)piperidine-1- 2H), 7.33 (m, 1H) carboxamideI-53B (3R)-N-((S)-3-cyclohexyl-1- 33 1.47 492 7.14-7.09 (m, 1H),6.97-6.93 (m, 2H), (methylamino)propan-2-yl)-3-((S)-1- 6.75-6.70 (m,1H), 6.49 (s, 2H), 4.11 (dm, (3-fluorophenyl)-1-hydroxy-5- J = 12.8 Hz,1H), 3.99-3.92 (m, 1H), methoxypentyl)piperidine-1- 3.76 (dm, J = 12.8Hz, 1H), 3.11 (t, J = 6.4 Hz, carboxamide 2H), 3.05 (s, 3H), 2.86 (dd, J= 12.8, 3.6 Hz, 1H), 2.79 (dd, J = 12.8, 9.6 Hz, 1H), 2.50 (s, 3H), 2.33(t, J = 12.2 Hz, 2H), 1.82-0.64 (m, 25H) I-54A(3R)-N-((S)-2-amino-5-methoxy-4,4- 127 1.38 500 0.84 (m), 0.98 (s), 1.00(s), 1.22-1.68 (m), dimethylpentyl)-3-((S)-1-(2,3- 1.96 (m), 2.18 (m),2.66 (m), 3.18 (d), difluorophenyl)-1-hydroxy-5- 3.24 (sd), 3.30 (m),3.38 (s), 3.84 (d), methoxypentyl)piperidine-1- 4.42 (d), 7.16 (m), 7.38(m). carboxamide I-55A 3-((S)-1-amino-3-cyclohexylpropan- 27 1.78 494−.032 (m), 0.35 (m), 0.86 (m), 3.26 (m), 2-ylamino)-4-(3-((2- 3.61 (m),4.03 (br s), 4.62 (br s), 7.30 (m)cyclopropylethoxy)(phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dione I-56A (3R)-3-(1-hydroxy-5-methoxy-1-(2- 33 1.41 496 0.91 (m), 1.75(m), 1.95 (m), 2.21 (m), phenoxyphenyl)pentyl)-N-(piperidin-3- 2.35 (m),2.87 (m), 3.2 (s), 3.84 (m), yl)piperidine-1-carboxamide 4.38 (br m),6.78 (d), 6.92 (m), 7.01 (d), 7.11 (m), 7.19 (m), 7.34 (m), 7.67 (m)I-57A (3R)-N-((S)-3-cyclohexyl-1- 33 1.72 498 0.82-0.93 (m), 1.98 (t),2.32 (s), 2.81 (s), (methylamino)propan-2-yl)-3-(4,4,4- 3.28 (m), 3.59(d), 4.25 (d), 6.19 (d), trifluoro-1-hydroxy-1-m- 7.03-7.17 (m), 9.29(br s), 9.91 (br s) tolylbutyl)piperidine-1-carboxamide I-58A^(be)3-((S)-1-amino-3-cyclohexylpropan- 26 1.43 498 8.20 (br s, 2H),7.37-7.19 (m, 5H), 4.58 (br 2-ylamino)-4-((R)-3-((R)-(3- s, 1H),4.00-3.62 (m, 2H), 3.57-2.90 (m,methoxypropoxy)(phenyl)methyl)piperidin- 10H)1-yl)cyclobut-3-ene-1,2-dione I-58B 3-((S)-1-amino-3-cyclohexylpropan-26 1.48 498 7.39-7.24 (m, 5H), 4.65 (m, 1H), 4.20 (brs,2-ylamino)-4-((R)-3-((R)-(3- 1H), 3.52-3.45 (m, 2H), 3.40 (m, 1H),methoxypropoxy)(phenyl)methyl)piperidin- 3.22-3.09 (m, 3H), 3.03-2.97(m, 1H) 1-yl)cyclobut-3-ene-1,2-dione I-58C^(f)3-((S)-1-amino-3-cyclohexylpropan- 26 1.48 498 7.38-7.24 (m, 5H), 4.66(m, 1H), 4.24 (m, 2-ylamino)-4-(3-((3- 1H), 3.53-3.35 (m, 3H), 3.30(3H), methoxypropoxy)(phenyl)methyl)piperidin- 3.22-3.07 (m, 3H), 2.99(m, 1H) 1-yl)cyclobut-3-ene-1,2-dione I-58D^(g)3-((S)-1-amino-3-cyclohexylpropan- 28 1.46 498 2.95 (m), 3.30 (s), 4.05(m), 7.10-7.50 (m) 2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dioneI-59A^(c) 3-((S)-1-amino-3-cyclohexylpropan- 28 1.37 500 1.80 (m), 3.30(s), 3.70 (m), 3.89 (br d), 2-ylamino)-4-(2-((3- 4.65 (m),methoxypropoxy)(phenyl)methyl)- morpholino)cyclobut-3-ene-1,2-dioneI-60A 4-(3-((3- 39 1.87 503 1.77 (m), 2.70 (m), 3.25 (s), 3.43 (m),methoxypropoxy)(phenyl)methyl)piperidin- 4.10 (m), 7.2-7.4 (m)1-yl)-N-((S)-1-amino-3- cyclohexylpropan-2-yl)-1,2,5- thiadiazol-3-amineI-61A 3-((3- 30 1.75 502 0.95 (m), 1.20 (m), 1.40 (m), 2.90 (m),methoxypropoxy)(phenyl)methyl)-N- 3.80 (m), 4.1 (m) 7.20-7.50 (m)(1-(butylamino)-3-cyclohexylpropan- 2-yl)piperidine-1-carboxamide I-62A3-((3- 30 1.74 502 1.10 (m), 2.10 (m), 3.80 (m), 4.1 (m)methoxypropoxy)(phenyl)methyl)-N- 7.20-7.50 (m) (3-cyclohexyl-1-(isobutylamino)propan-2- yl)piperidine-1-carboxamide I-63A(3R)-N-((S)-3-cyclohexyl-1- 30 1.59 502(dimethylamino)propan-2-yl)-3-((R)- 5-ethoxy-1-hydroxy-1-phenylpentyl)piperidine-1- carboxamide I-64A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.55 508 7.43 (s, 1H), 7.32-7.25(m, 2H), 7.22 (dd, hydroxy-5-methoxypentyl)-N-((S)-3- 1H), 4.31 (d, 1H),4.15 (m, 1H), 3.97 (d, cyclohexyl-1-(methylamino)propan- 1H), 3.25 (s,3H), 3.08-2.95 (m, 2H), 2-yl)piperidine-1-carboxamide 2.67 (s, 3H), 2.52(m, 2H). I-65A 3-((3-ethoxypropoxy)(3,4- 33 1.77 510 2.63 (m), 3.24 (m),3.27 (m), 3.37 (m), difluorophenyl)methyl)-N-((S)-3- 4.23 (m), 4.36 (m),7.04-7.24 (m) cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-66A (3R)-N-((S)-3-cyclohexyl-1- 33 510271 (s, 3H), 2.92 (dd, 1H), 3.06 (dd),(methylamino)propan-2-yl)-3-((S)-1- 3.25 (s, 3H), 3.98 (br d, 1H), 4.129m, 1H), (2,5-difluorophenyl)-1-hydroxy-5- 4.31 (br d, 1H), 7.01 (m,2H), 7.31 (m, methoxypentyl)piperidine-1- 1H) carboxamide I-67A^(b)(3R)-N-((S)-3-(4,4- 33 510 2.31 (t, 1H), 2.53 (t, 1H), 2.76 (s, 3H),difluorocyclohexyl)-1- 2.89 (m, 1H), 3.29 (s, 3H), 3.31 (t, 1H),(methylamino)propan-2-yl)-3-((S)-1- 3.75 (br d, 1H), 4.24 (m, 2H), 6.16(m, hydroxy-5-methoxy-1- 1H) phenylpentyl)piperidine-1- carboxamideI-68A (3R)-N-((S)-3-cyclohexyl-1- 33 510 2.55 (t, 3H), 2.79 (s, 3H),2.91 (m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 3.28 (s, 3h), 3.31 (t,1H), 3.78 (br d, 1H), (3,4-difluorophenyl)-1-hydroxy-5- 4.27 (m, 2H),6.11 (m, 1H), 7.32 (m, 3H) methoxypentyl)piperidine-1- carboxamide I-69A3-((S)-1-amino-3-cyclohexylpropan- 28 1.71 510 7.26-7.08 (m), 4.52 (m),3.01-2.87 (m), 2-ylamino)-4-(3-(1-hydroxy-1- 1.90-0.70 (m)phenylheptyl)piperidin-1-yl)cyclobut- 3-ene-1,2-dione I-70A^(b)3-((2S,3S)-3-amino-1- 24 512 4.68 (m), 4.21 (m), 3.55-3.05 (m, 8H),cyclohexylbutan-2-ylamino)-4-(3- 3.32 (s, 3H), 2.05-0.75 (m, 21H) ((3-methoxypropoxy)(phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dioneI-70B^(b) 3-((2S,3R)-3-amino-1- 25 512 4.68 (m, 3H), 4.21 (m, 1H),3.55-3.10 (m, cyclohexylbutan-2-ylamino)-4-(3- 8H), 3.32 (s, 3H),1.95-0.80 (m, 21H) ((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-71A 3-(3-((3- 28 1.5 512 2.75 (m), 3.30(s), 3.50 (s), 4.20 (m), methoxypropoxy)(phenyl)methyl)piperidin-7.20-7.50 (m) 1-yl)-4-(N-((S)-1-amino-3- cyclohexylpropan-2-yl)-N-methylamino)cyclobut-3-ene-1,2- dione I-72A(3R)-3-((S)-1-(2-(p-tolyloxy)-5- 33 1.57 512 1.18 (d), 2.32 (s), 2.34(s), 2.64 (s), methylphenyl)-1-hydroxy-5- 3.24 (s), 3.86 (d), 4.0 (m),4.36 (d), 6.60 (d), methoxypentyl)-N-((S)-1- 6.78 (d), 6.98 (dd), 7.14(d), 7.42 (d) (methylamino)propan-2- yl)piperidine-1-carboxamide + ~10%of alcohol epimer I-73A 3-((S)-3-cyclohexyl-1- 28 1.53 512 2.80 (s),3.38 (s), 4.05 (br m), (methylamino)propan-2-ylamino)-4- 7.20-7.50 (m)(3-((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-74A 3-((3-methoxypropoxy)(2- 33 1.71 5140.8-1.9 (m), 2.8 (m), 3.28 (s), 4.03 (m),(trifluoromethyl)phenyl)methyl)- 4.40 (m), 4.56 (m), 7.48 (m), 7.70 (m)N-((S)-1-amino-3-cyclohexylpropan-2- yl)piperidine-1-carboxamide I-75A3-((S)-1-amino-3-cyclohexylpropan- 26 1.49 516 0.9 (m), 3.34 (s), 4.02(m), 4.67 (m), 2-ylamino)-4-(3-((3- 7.12 (m), 7.30 (m)methoxypropoxy)(4- fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-76A 3-((S)-1-amino-3-cyclohexylpropan- 231.48 516 0.9-2.1 (m), 3.0 (m), 3.14 (m), 3.36 (s), 2-ylamino)-4-(3-((3-3.52 (m), 4.44 (d), 4.64 (m), 7.12 (t), methoxypropoxy)(2- 7.24 (t),7.36 (m), 7.41 (m) fluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-77A 3-((3- 30 1.83 516 0.90 (m), 1.80 (m),3.30 (s), 4.17 (br m), methoxypropoxy)(phenyl)methyl)-N- 7.20-7.60 (m)(3-cyclohexyl-1- (isopentylamino)propan-2- yl)piperidine-1-carboxamideI-78A^(b) 3-((3- 30 1.83 516 0.95 (m), 1.20 (m), 1.35-1.45 (m),methoxypropoxy)(phenyl)methyl)-N- 2.90 (m), 3.80 (m), 4.1 (m) 7.20-7.50(m) (3-cyclohexyl-1- (pentylamino)propan-2- yl)piperidine-1-carboxamideI-79A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33 516 1.25 (d, 6H), 2.51 (t, 1H),2.81 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.27 (s, 3H), 3.31 (t,1H), 3.75 (br d, 1H), hydroxy-1-(3-isopropylphenyl)-5- 4.23 (m, 2H),6.06 (br s, 1H), 7.12 (m methoxypentyl)piperidine-1- 3H), 7.23 (t, 1H)carboxamide I-80A (3R)-3-((R)-1-(3-chlorophenyl)- 33 1.72 518 0.91 (m),1.03 (m), 2.49 (t), 2.58 (q), 4,4,4-trifluoro-1-hydroxybutyl)- 2.71 (s),2.93 (t), 3.07 (ap d), 3.30-3.33 (m), N-((S)-3-cyclohexyl-1- 3.84 (d),3.96 (d) 4.13 (m), 4.33 (d), (methylamino)propan-2- 4.48 (d), 7.29 (m),7.34 (m), 7.46 (ap s) yl)piperidine-1-carboxamide I-81A(3R)-3-((S)-1-(5-chloro-2- 33 1.53 518 1.18 (d), 2.64 (s), 3.24 (s),3.85 (d), phenoxyphenyl)-1-hydroxy-5- 4.06 (m), 4.38 (d), 6.66 (d), 6.94(d), 7.14 (m), methoxypentyl)-N-((S)-1- 7.38 (dd), 7.64 (d)(methylamino)propan-2- yl)piperidine-1-carboxamide + ~10% of alcoholepimer I-82A (3R)-3-(1-(3-chlorophenyl)-5- 33 1.95 518 −.0.84 (m), 0.33(,), 0.57 (m), 2.53 (t), cyclopropyl-1-hydroxypentyl)- 2.68 (s), 2.91(m), 3.04 (m), 3.29 (m), 3.47 (m), N-((S)-3-cyclohexyl-1- 3.96 (d), 4.11(m), 4.27 (d), 7.20-7.31 (m), (methylamino)propan-2- 7.41 (ap s)yl)piperidine-1-carboxamide I-83A 3-((3-methoxypropoxy)(2- 127 1.72 5220.94 (m), 2.31 (m), 2.49 (m), 2.65 (m), phenylphenyl)methyl)-N-((S)-2-3.30 (m), 7.16-7.78 (m) amino-3- cyclohexylpropyl)piperidine-1-carboxamide I-84A 3-((3-methoxypropoxy)(2-(2- 33 1.87 524 2.67 (m), 3.02(m), 3.30 (m), cyclopropylethynyl)phenyl)methyl)- 3.41-3.49 (m), 3.79(d), 3.95 (m), 4.07 (m), 4.18 (d), N-((S)-3-cyclohexyl-1- 4.33 (d), 4.59(m), 7.27 (m), 7.34 (m) (methylamino)propan-2-yl)piperidine-1-carboxamide I-85A 3-(3-cyclohexyl-1- 28 1.55 526 1.30(m), 3.00-3.20 (m), 3.30 (s), (ethylamino)propan-2-ylamino)-4- 4.10 (m),7.02-7.45 (m) (3-((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-86A (3R)-3-((S)-1-hydroxy-5-methoxy-1-33 1.56 526 0.78 (d), 0.84 (d), 2.64 (s), 3.24 (s),(2-phenoxyphenyl)pentyl)-N-((S)-4- 4.00 (m), 4.26 (d), 6.74 (d), 6.92(d), 7.1 (m), methyl-1-(methylamino)pentan-2- 7.38 (dd), 7.64 (d)yl)piperidine-1-carboxamide + ~10% of alcohol epimer I-86B(3R)-3-((S)-1-hydroxy-5-methoxy-1- 33 1.56 526 0.78 (d), 0.84 (d), 2.64(s), 3.24 (s), (2-phenoxyphenyl)pentyl)-N-((S)-4- 4.00 (m), 4.26 (d),6.68 (s), 6.74 (d), 6.92 (d), methyl-1-(methylamino)pentan-2- 7.1 (m),7.38 (dd), 7.64 (d) yl)piperidine-1-carboxamide I-87A(3R)-N-((S)-1-amino-5-methoxy-4,4- 33 1.38 500 0.84 (m), 0.98 (s),1.20-1.64 (m), dimethylpentan-2-yl)-3-((S)-1-(2,3- 1.98 (m), 2.18 (m),2.64 (m), 2.78 (dd), difluorophenyl)-1-hydroxy-5- 2.84 (dd), 2.98 (dd),3.10 (s), 3.24 (s), methoxypentyl)piperidine-1- 3.30 (m), 3.34 (s), 3.96(d), 4.12 (m), 4.38 (d), carboxamide 7.14 (m), 7.36 (m). I-88A^(b)(3R)-N-((S)-3-(4,4- 33 528 2.54 (t, 1H), 2.81 (s, 3H), 2.89 (m, 1H),difluorocyclohexyl)-1- 3.28 (s, 3H), 3.32 (t, 1H), 3.73 (br d, 1H),(methylamino)propan-2-yl)-3-((S)-1- 4.22 (m, 2H), 6.22 (br s, 1H), 6.93(t, 1H), (3-fluorophenyl)-1-hydroxy-5- 7.07 (m, 2H), 7.29 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-89A3-((S)-1-amino-3-cyclohexylpropan- 28 1.43 534 7.31-7.24 (m), 6.90-6.83(m), 2-ylamino)-4-(3-((3- 4.56-4.43 (m), 3.38-2.83 (m), 2.30 (m),methoxypropoxy)(2,4- 1.79-0.78 (m) difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-90A 3-((S)-1-amino-3-cyclohexylpropan- 281.48 534 7.13-7.07 (m), 4.55 (m), 4.38-4.35 (m), 2-ylamino)-4-(3-((3-3.44-2.86 (m), 1.93-0.78 (m) methoxypropoxy)(3,4-difluorophenyl)methyl)piperidin-1- yl)cyclobut-3-ene-1,2-dione I-91A(3R)-N-((S)-1- 33 1.51 535 0.9-2.0 (m), 2.58 (m), 2.98 (m), 3.16 (m),(carbamoylmethylamino)-3- 3.24 (s), 3.80 (d), 3.86 (d), 3.94 (d),cyclohexylpropan-2-yl)-3-((S)-1-(3- 4.14 (m), 4.32 (d), 6.96 (m), 7.16(m), 7.32 (m) fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-92A 3-(3-cyclohexyl-1- 28 1.57 540 0.90 (m), 1.45 (m),2.95 (m), 3.30 (s), (propylamino)propan-2-ylamino)-4- 4.10 (m),7.20-7.40 (m) (3-((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-93A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33542 2.55 (t, 1H), 2.82 (s, 3H), 3.29 (s, 3H),(methylamino)propan-2-yl)-3-((S)-1- 3.32 (t 1H), 3.72 (br d, 1H), 4.25(m, 2H), (3-(trifluoromethyl)phenyl)-1- 6.05 (s, 1H), 7.43 (m, 1H), 7.50(m, 2H), hydroxy-5- 7.64 (s, 1H) methoxypentyl)piperidine-1- carboxamideI-93A (3R)-N-((S)-3-cyclohexyl-1- 33 542 2.71 (s), 2.72 (s), 3.26 (s),3.84 (br d), (methylamino)propan-2-yl)-3-(1-(3- 3.96 (br d), 4.12 (brd), 4.33 (br d), (trifluoromethyl)phenyl)-1-hydroxy- 4.48 (br d)5-methoxypentyl)piperidine-1- carboxamide I-94A 3-(3-cyclohexyl-1- 281.6 554 1.01 (m), 2.05 (m), 2.95 (m), 3.30 (s),(isobutylamino)propan-2-ylamino)- 4.01 (m), 7.02-7.45 (m) 4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dioneI-95A 3-(3-(butylamino)-1- 28 1.66 554 0.90 (m), 1.33 (m), 1.45 (m),2.90 (m), cyclohexylpropan-2-ylamino)-4-(3- 3.30 (s), 4.10 (m),7.20-7.40 (m) ((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-96A (3R)-3-((S)-1-(2-(p-tolyloxy)-5- 331.74 554 0.78 (d), 0.84 (d), 2.32 (s), 2.34 (s),methylphenyl)-1-hydroxy-5- 2.64 (s), 3.24 (s), 4.0 (m), 4.24 (d), 6.58(d), methoxypentyl)-N-((S)-4-methyl-1- 6.78 (d), 6.96 (dd), 7.16 (d),7.42 (d) (methylamino)pentan-2- yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-97A (3R)-3-((S)-1-(5-chloro-2- 33 1.67 560 0.78 (d),0.82 (d), 1.2-1.7 (m), 2.62 (s), phenoxyphenyl)-1-hydroxy-5- 3.24 (s),4.0 (m), 4.24 (d), 6.64 (d), methoxypentyl)-N-((S)-4-methyl-1- 6.94 (d),7.16 (m), 7.38 (dd), 7.64 (d) (methylamino)pentan-2-yl)piperidine-1-carboxamide + ~10% of alcohol epimer I-98A3-(3-cyclohexyl-1- 28 1.67 562 1.05 (t), 2.75 (m), 3.35 (m), 3.38 (s),(methylamino)propan-2-ylamino)-4- 4.10 (d), 7.00-7.40 (m)(3-((3-ethoxypropoxy)(3,4- difluorophenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-99A 3-((S)-1-amino-3-cyclohexylpropan- 261.61 566 0.9-2.1 (m), 3.35 (s), 4.46 (m), 4.65 (m), 2-ylamino)-4-(3-((3-7.52 (t), 7.71 (m) methoxypropoxy)(2-(trifluoromethyl)phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dioneI-100A (3R)-N-((S)-3-cyclohexyl-1- 33 1.72 566 0.8-1.7 (m), 1.98 (m),2.64 (s), 3.24 (s), (methylamino)propan-2-yl)-3-((S)-1- 4.0 (m), 4.26(d), 6.68 (d), 6.92 (d), hydroxy-5-methoxy-1-(2- 7.1 (m), 7.36 (dd),7.62 (d) phenoxyphenyl)pentyl)piperidine-1- carboxamide + ~10% ofalcohol epimer I-101A 3-(1-cyclohexyl-3- 28 1.71 568 0.90 (m), 1.01 (m),1.25 (m), 1.50 (m), (pentylamino)propan-2-ylamino)-4- 2.90 (m), 3.30(s), 4.10 (m), 7.20-7.40 (m) (3-((3-methoxypropoxy)(phenyl)methyl)piperidin- 1-yl)cyclobut-3-ene-1,2-dioneI-102A 3-(1-cyclohexyl-3- 28 1.72 568 0.90 (m), 1.20 (m), 1.40 (m), 1.80(m), (isopentylamino)propan-2-ylamino)- 3.10 (m), 3.30 (s), 4.10 (m),7.20-7.50 (m) 4-(3-((3- methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione I-103A (3R)-3-((S)-1-(2-(p-tolyloxy)-5- 331.87 594 0.8-1.7 (m), 2.32 (s), 2.34 (s), 2.64 (s),methylphenyl)-1-hydroxy-5- 3.24 (s), 4.0 (m), 4.24 (d), 6.58 (d),methoxypentyl)-N-((S)-3-cyclohexyl- 6.78 (d), 6.96 (dd), 7.16 (d), 7.42(d) 1-(methylamino)propan-2- yl)piperidine-1-carboxamide + ~10% ofalcohol epimer I-104A (3R)-3-((S)-1-(5-chloro-2- 33 1.83 600 0.8-1.7(m), 2.64 (s), 3.24 (s), 4.0 (m), phenoxyphenyl)-1-hydroxy-5- 4.24 (d),6.64 (d), 6.96 (d), 7.16 (m), methoxypentyl)-N-((S)-3-cyclohexyl- 7.38(dd), 7.64 (d) 1-(methylamino)propan-2- yl)piperidine-1-carboxamide +~10% of alcohol epimer I-105A N-((S)-3-cyclohexyl-1- 42 1.87 449 8.33(d, J = 8.5 Hz, 1H), 7.82-7.13 (m, (methylamino)propan-2-yl)-3-((pent-9H), 5.75-5.68 (m, 1H), 5.36 (s, 1H), 4- 4.92-4.84 (m, 2H), 4.43-4.40(m, 1H), enyloxy)(phenyl)methyl)benzamide 3.39 (t, J = 6.4 Hz, 2H),3.09-2.93 (m, 2H), 2.61 (s, 3H), 2.10-2.05 (m, 2H), 1.77-0.81 (m, 15H).I-106A N-((S)-3-cyclohexyl-1- 130 1.67 451 8.29 (d, J = 8.2 Hz, 1H),7.71-7.05 (m, (methylamino)propan-2-yl)-3-(5- 9H), 4.43-4.41 (m, 1H),3.91 (t, J = 7.9 Hz, methoxy-1-phenylpentyl)benzamide 1H), 3.26 (t, J =6.4 Hz, 2H), 3.18 (s, 3H), 3.10-2.92 (m, 2H), 2.616, 2.613 (s, 3H),2.06-2.00 (m, 2H), 1.77-0.81 (m, 17H). I-107A3-((2-ethoxyethoxy)(phenyl)methyl)- 42 1.65 453 7.83-7.16 (m, 9H), 5.45,5.43 (s, 1H), N-((S)-3-cyclohexyl-1- 4.41 (br s, 1H), 2.61, 2.59 (s,3H). (methylamino)propan-2- yl)benzamide I-108A 3-(1-(2- 33 1.36 4627.39-7.34 (m), 7.07 (t), 6.77 (m), 3.20 (m),(cyclopropylmethoxy)phenyl)-1- 3.13 (s), 2.60 (s), 0.73 (br s), 0.51(d), hydroxy-5-methoxypentyl)-N-((S)-1- 0.23 (m). (methylamino)propan-2-yl)piperidine-1-carboxamide I-109A (3R)-3-((S)-1-hydroxy-5-methoxy-1- 331.49 462 0.96 (s), 1.00-1.78 (m), 1.92 (m), 2.34 (s),m-tolylpentyl)-N-((S)-4,4-dimethyl-1- 2.48 (m), 2.70 (s), 2.92 (dd),3.02 (dd), (methylamino)pentan-2- 3.24 (s), 3.26 (t), 3.98 (d), 4.18(m), yl)piperidine-1-carboxamide 4.26 (d), 7.02 (d), 7.14 (d), 7.20 (m)I-110A^(b) N-((S)-3-cyclohexyl-1- 37 464.3 2.03 (m, 1H), 3.28 (s, 3H),(methylamino)propan-2-yl)-3-(5- 5.14&5.73 (m, 1H), 6.76 (m, 1H),methoxy-1-(thiophen-2- 6.92 (m, 1H), 7.14 (m, 1H), 8.21 (brs, 1H),yl)pentyl)piperidine-1-carboxamide 9.84 (brs, 1H) I-111AN-((S)-3-cyclohexyl-1- 33 1.42 466 4.11 (m, 1H), 3.72 (m, 1H), 3.41 (t,2H), (methylamino)propan-2-yl)-3-(1,1,1- 3.05 (d, 1H), 2.69 (s, 3H),1.92 (d, 1H), trifluoro-2-hydroxy-6- 1.02 (q, 1H), 0.89 (m, 1H)methoxyhexan-2-yl)piperidine-1- carboxamide I-112A 3-((2- 145 1.37 4668.34-8.29 (m, 1H), 7.86-7.12 (m, 9H), acetamidoethoxy)(phenyl)methyl)-5.76 (s, 1H), 5.41 (d, J = 2 Hz, 1H), N-((S)-1-cyclohexyl-3- 4.45-4.38(m, 1H), 3.45-3.43 (m, 2H), (methylamino)propan-2- 3.35-3.31 (m, 2H),3.10-3.06 (m, 1H), yl)benzamide 3.00-2.93 (m, 1H), 2.62 (s, 3H), 1.844,1.839 (s, 3H), 1.77-0.82 (m, 13H). I-113A(3R)-3-((S)-1-(3-fluorophenyl)-1- 33 1.45 466 0.96 (s), 1.08-1.98 (m),2.44 (m), 2.64 (s), hydroxy-5-methoxypentyl)-N-((S)- 2.86 (m), 2.98 (m),3.24 (s), 3.26 (t), 4,4-dimethyl-1- 3.94 (d), 4.14 (m), 4.24 (d), 6.86(m), 7.08 (m), (methylamino)pentan-2- 7.26 (m)yl)piperidine-1-carboxamide I-114A N-((S)-3-cyclohexyl-1- 128 1.47 4678.26 (d, J = 8.2 Hz, 1H), 7.89-7.03 (m, (methylamino)propan-2-yl)-3-(1-9H), 4.40-4.38 (m, 1H), 3.23 (t, J = 6.4 Hz, hydroxy-5-methoxy-1- 2H),3.15 (s, 3H), 3.06-2.91 (m, 2H), phenylpentyl)benzamide 2.584, 2.579 (s,3H), 2.23 (t, J = 8.2 Hz, 2H), 1.74-0.78 (m, 17H). I-115A 3-((3- 42 1.74467 8.32 (d, J = 7.6 Hz, 1H), 7.82-7.13 (m,ethoxypropoxy)(phenyl)methyl)- 9H), 5.37 (s, 1H), 4.43-4.38 (m, 1H),N-((S)-3-cyclohexyl-1- 3.48-3.44 (m, 4H), 3.37 (q, J = 7.0 Hz,(methylamino)propan-2- 2H), 3.07 (dd, J = 12.6, 3.2 Hz, 1H),yl)benzamide 2.95 (dd, J = 12.4, 10.4 Hz, 1H), 2.61 (s, 3H), 1.05 (t, J= 7.0 Hz, 3H), 1.83-0.81 (m, 15H). I-116A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.48 469 0.92 (m, 6 H), 1.2-2.0 (m)2.53 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-4- 3.8 (m, 1H) 7.2-7.6 (m,4 H) methyl-1-(methylamino)pentan-2- yl)piperidine-1-carboxamide I-117A(3R)-3-((S)-1-(2,3-difluorophenyl)-1- 33 1.37 470 7.23 (m), 7.06-6.96(m), 4.22 (d), hydroxy-5-methoxypentyl)-N-((S)-4- 3.97 (m), 3.83 (d),3.17 (s), 3.12 (s), 2.94 (d), methyl-1-(methylamino)pentan-2- 2.80 (t),2.65 (t), 2.60 (s), 2.50 (s), yl)piperidine-1-carboxamide 0.83 (m).I-118A (3R)-3-((S)-1-(benzofuran-7-yl)-1- 33 1.32 474 0.98 (d, 3H), 1.01(d, 3H), 2.72 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-4- 3.19 (s, 3H),3.95 (br d, 1H), 4.10 (m, methyl-1-(methylamino)pentan-2- 1H), 4.42 (brd, 1H), 6.86 (d, 1H), yl)piperidine-1-carboxamide 7.21 (m, 1H), 7.43 (d,1H), 7.52 (d, 1H), 7.69 (d, 1H) I-119A^(b) (3R)-N-((S)-3-cyclohexyl-1-121 475.3 2.09 (m, 3H), 2.41 (t, 3H), 2.56 (t, 1H),(methylamino)propan-2-yl)-3-((S)-1- 2.77 (s, 3H), 3.08 (m, 2H), 3.78 (d,1H), hydroxy-5-methoxy-1-(pyridin-2- 4.23 (m, 1H), 4.47 (d, 1H), 6.01(m, 1H), yl)pentyl)piperidine-1-carboxamide 7.83 (dd, 2H), 8.36 (t, 1H),8.42 (m, 1H), 8.84 (d, 1H), 9.05 (brs, 1H) I-120A (3R)-3-(1-(2-(2- 331.45 476 7.44-7.36 (m), 7.10 (m), 7.10 (m), cyclopropylethoxy)phenyl)-1-4.40 (d), 4.19 (d), 3.94 (m), 3.84 (d), 3.68 (m),hydroxy-5-methoxypentyl)-N-((S)-1- 3.48 (d), 3.21 (m), 3.16 (m), 3.13(s), (methylamino)propan-2- 3.00-2.87 (m), 2.61 (s), 2.53 (s), 0.76 (m),yl)piperidine-1-carboxamide 0.41 (q), 0.05 (m). I-121A (3R)-3-(1-(2- 331.42 476 7.41 (d), 7.35 (d), 7.06 (m), 6.76 (m),(cyclopentyloxy)phenyl)-1-hydroxy- 4.37 (d), 4.17 (d), 4.00 (m), 3.83(d), 3.69 (m), 5-methoxypentyl)-N-((S)-1- 3.19 (m), 3.16 (m), 3.12 (s),2.59 (s), (methylamino)propan-2- 2.52 (s). yl)piperidine-1-carboxamideI-122A 3-((3- 124 1.73 476 2.60 (s), 2.63 (s), 3.4 (br m), 4.91 (m),methoxypropoxy)(phenyl)methyl)- 4.06 (m), 4.25 (br d), 4.33 (br d), 5.08(br N-((S)-3-cyclohexyl-1- m), 7.18-7.26 (m) (methylamino)propan-2-yl)piperidine-1-carbothioamide I-123A (3R)-N-((S)-1-amino-3- 33 1.45 4787.22-7.16 (m, 1H), 7.03-7.00 (m, 2H),cyclohexylpropan-2-yl)-3-((S)-1-(3- 6.83-6.78 (m, 1H), 4.17 (d, J = 13.2Hz, fluorophenyl)-1-hydroxy-5- 1H), 3.96-3.89 (m, 1H), 3.83 (d, J = 12.9Hz, methoxypentyl)piperidine-1- 1H), 3.12 (s, 3H), 2.88 (dd, J = 12.7,carboxamide 3.4 Hz, 1H), 2.71 (dd, J = 12.4, 9.8 Hz, 1H), 2.44-2.32 (m,2H), 1.89-0.71 (m, 24H). I-124A (3R)-3-(1-hydroxy-5-methoxy-1-(2- 331.48 478 7.43-7.36 (m), 7.09 (m), 6.80, (m),(neopentyloxy)phenyl)pentyl)- 3.19 (m), 3.10 (m), 2.59 (s), 2.51 (s),0.96 (m). N-((S)-1-(methylamino)propan-2- yl)piperidine-1-carboxamideI-125A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 478.3 2.17 (s, 3H), 2.25 (m,1H), 2.97 (m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 3.18 (m, 1H),3.30 (s, 3H), 3.41 (m, 1H), hydroxy-5-methoxy-1-(1-methyl-1H- 3.69 (m,1H), 4.02 (m, 2H), 4.32 (m, 1H), imidazol-2-yl)pentyl)piperidine-1- 5.78(m, 1H), 6.94 (m, 1H), 7.33 (m, 1H), carboxamide 8.38 (brs, 1H), 9.10(brs, 1H) I-126A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 480.2 0.92 (m, 5H),2.85 (m, 3H), 3.18 (m, 2H), (methylamino)propan-2-yl)-3-((S)-1- 3.26 (s,3H), 4.05 (m, 2H), 4.23 (m, 3H), hydroxy-5-methoxy-1-(thiophen-2- 6.78(m, 1H), 7.00 (m, 1H), 7.52 (m, 1H), yl)pentyl)piperidine-1-carboxamide7.70 (m, 1H) I-127A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 480.3 2.53 (m,2H), 2.78 (s, 3H), 3.28 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1-3.68 (m, 1H), 4.12 (m, 1H), 4.32 (m, 2H),hydroxy-5-methoxy-1-(thiophen-3- 6.18 (m, 1H), 6.77 (m, 1H), 6.97 (m,1H), yl)pentyl)piperidine-1-carboxamide 7.18 (m, 1H) I-128AN-((S)-3-cyclohexyl-1- 129 1.62 481 8.25 (d, J = 8.8 Hz, 1H), 7.92-6.92(m, (methylamino)propan-2-yl)-3-(1- 8H), 4.44-4.41 (m, 1H), 3.28 (t, J =6.4 Hz, hydroxy-5-methoxy-1-m- 2H), 3.20 (s, 3H), 3.11-2.93 (m, 2H),tolylpentyl)benzamide 2.635 2.628 (s, 3H), 2.26 (t, J = 8.0 Hz, 2H),2.21 (s, 3H), 1.78-0.82 (m, 17H). I-129A N-((S)-3-cyclohexyl-1- 129 1.61481 8.24 (d, J = 8.4 Hz, 1H), 7.79-6.96 (m,(methylamino)propan-2-yl)-3-(1- 8H), 4.42-4.39 (m, 1H), 3.27 (t, J = 6.4Hz, hydroxy-5-methoxy-1-o- 2H), 3.20 (s, 3H), 3.10-2.95 (m, 2H),tolylpentyl)benzamide 2.635, 2.622 (s, 3H), 2.35-2.16 (m, 2H), 1.90 (s,3H), 1.75-0.82 (m, 17H). I-130A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33 481.32.17 (m, 2H), 3.28 (s, 3H), 3.75 (m, 1H),(methylamino)propan-2-yl)-3-((S)-1- 4.27 (m, 2H), 6.07 (m, 1H), 7.76 (m,1H), hydroxy-5-methoxy-1-(thiazol-2- 9.10 (brs, 1H), 9.73 (brs, 1H)yl)pentyl)piperidine-1-carboxamide I-131A (3R)-3-((S)-1-(2-(3- 121 482.30.92 (m, 1H), 1.14 (m, 3H), 1.26 (m, 4H),methylphenyl)phenyl)-1-hydroxy-5- 1.45 (m, 2H), 1.59 (m, 3H), 1.74 (m,1H), methoxypentyl)-N-((S)-1- 2.35 (s, 3H), 2.56 (m, 1H), 2.68 (s, 3H),(methylamino)propan-2- 2.74 (m, 1H), 2.91 (m, 1H), 3.03 (m, 1H),yl)piperidine-1-carboxamide 3.26 (m, 3H), 3.95 (m, 3H), 6.95 (m, 3H),7.19 (m, 3H), 7.32 (t, 1H), 7.72 (d, 1H) I-132A (3R)-3-((S)-1-(2-(4- 121482.3 0.92 (m, 1H), 1.14 (d, 3H), 2.36 (s, 3H),methylphenyl)phenyl)-1-hydroxy-5- 2.55 (m, 1H), 2.68 (s, 3H), 2.73 (m,1H), methoxypentyl)-N-((S)-1- 2.90 (m, 1H), 3.04 (m, 1H), 3.94 (m, 3H),(methylamino)propan-2- 6.92 (m, 1H), 6.95-7.24 (m, 5H), 7.32 (t, 1H),yl)piperidine-1-carboxamide 7.72 (m, 1H) I-133A (3R)-3-((S)-1-(2-(2- 121482.3 0.94 (m, 1H), 1.15 (d, 3H), 1.30 (m, 3H),methylphenyl)phenyl)-1-hydroxy-5- 2.58 (m, 1H), 2.68 (s, 3H), 2.75 (m,1H), methoxypentyl)-N-((S)-1- 2.94 (m, 1H), 3.01 (m, 1H), 3.26 (m, 3H),(methylamino)propan-2- 3.87 (m, 1H), 4.02 (m, 2H), 6.96 (m, 1H),yl)piperidine-1-carboxamide 7.10-7.28 (m, 4H), 7.35 (m, 2H), 7.74 (m,1H) I-134A (3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.52 482 0.98 (s),1.10-1.78 (m), 1.92 (m), hydroxy-5-methoxypentyl)-N-((S)- 2.48 (m), 2.68(s), 2.92 (dd), 3.02 (dd), 4,4-dimethyl-1- 3.24 (s), 3.26 (t), 3.98 (d),4.18 (m), 4.28 (d), (methylamino)pentan-2- 7.22-7.34 (m), 7.42 (s)yl)piperidine-1-carboxamide I-135A (3R)-3-((S)-1-(2,3-difluorophenyl)-1-33 1.44 484 7.24 (m) 7.03 (m), 4.23 (d), 4.08 (t),hydroxy-5-methoxypentyl)-N-((S)- 3.88 (d), 3.19 (s), 3.4 (s), 2.59 (s),0.87 (s). 4,4-dimethyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-136A (R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-33 1.5 484 7.65 (dd, 1H), 7.28 (d, 1H), 7.16 (td, 2H),1-hydroxy-5-methoxypentyl)-N-(2- 7.08-7.03 (m, 2H), 6.73 (d, 1H), 6.57(d, aminoethyl)-N-methylpiperidine-1- 1H), 4.01 (d, 1H), 3.38 (td, 2H),3.24 (s, carboxamide 3H), 3.09 (t, 2H), 2.87 (s, 3H), 2.24 (s, 3H), 0.96(m, 1H). I-137A N-((S)-3-cyclohexyl-1- 129 1.54 485 8.29-6.80 (m, 9H),4.40 (br s, 1H), (methylamino)propan-2-yl)-3-(1-(3- 3.17 (s, 3H), 2.61(s, 3H). fluorophenyl)-1-hydroxy-5- methoxypentyl)benzamide I-138AN-((S)-3-cyclohexyl-1- 129 1.53 485 8.28-6.87 (m, 9H), 4.43-4.39 (m,1H), (methylamino)propan-2-yl)-3-(1-(4- 3.17 (s, 3H), 2.61 (s, 3H).fluorophenyl)-1-hydroxy-5- methoxypentyl)benzamide I-139A^(b)(3R)-3-((S)-1-hydroxy-5-methoxy-1- 119 485.3 0.85 (t, 6H), 2.06 (m, 2H),2.30 (m, 3H), (quinolin-8-yl)pentyl)-N-((S)-4- 2.70 (s, 3H), 2.99 (m,1H), 3.14 (m, 1H), methyl-1-(methylamino)pentan-2- 3.22 (s, 3H), 3.85(m, 1H), 4.16 (m, 1H), yl)piperidine-1-carboxamide 4.43 (m, 1H), 6.16(m, 1H), 7.70 (d, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.70 (d, 1H), 8.80(m, 1H), 9.14 (m, 1H), 9.28 (m, 1H) I-140A (3R)-3-((S)-1-(2-(2- 121486.3 0.95 (m, 3H), 1.15 (d, 3H), 2.56 (m, 1H),fluorophenyl)phenyl)-1-hydroxy-5- 2.68 (s, 3H), 2.74 (m, 1H), 2.92 (m,1H), methoxypentyl)-N-((S)-1- 3.05 (m, 1H), 3.25 (m, 3H), 3.86 (m, 1H),(methylamino)propan-2- 4.03 (m, 2H), 6.98 (m, 1H), 7.20 (m, 4H),yl)piperidine-1-carboxamide 7.37 (m, 2H), 7.75 (m, 1H) I-141A^(b)(3R)-3-((S)-1-(3-fluoro-2- 121 486.2 1.05 (m, 1H), 1.22 (d, 3H), 1.48(m, 2H), phenylphenyl)-1-hydroxy-5- 1.69 (m, 4H), 2.55 (m, 1H), 2.70 (s,3H), methoxypentyl)-N-((S)-1- 2.95 (m, 1H), 3.15 (m, 1H), 3.28 (s, 3H),(methylamino)propan-2- 3.32 (m, 2H), 3.71 (m, 1H), 3.86 (m, 1H),yl)piperidine-1-carboxamide 4.18 (m, 1H), 5.62 (m, 1H), 7.03 (t, 1H),7.12-7.48 (m, 7H), 8.58 (brs, 1H), 9.50 (brs, 1H) I-142A(3R)-3-((S)-1-(2-(3- 121 486.3 1.16 (d, 3H), 1.78 (m, 1H), 2.58 (m, 1H),fluorophenyl)phenyl)-1-hydroxy-5- 2.68 (s, 3H), 3.00 (m, 2H), 3.28 (s,3H), methoxypentyl)-N-((S)-1- 3.97 (m, 1H), 4.03 (m, 2H),(methylamino)propan-2- 6.73-7.12 (m, 4H), 7.23 (m, 1H), 7.35 (m, 2H),yl)piperidine-1-carboxamide 7.71 (m, 1H) I-143A (3R)-3-((S)-1-(2-(4- 121486.2 1.15 (m, 3H), 1.76 (m, 1H), 2.53 (m, 1H),fluorophenyl)phenyl)-1-hydroxy-5- 2.57 (s, 3H), 2.97 (m, 2H), 3.28 (m,3H), methoxypentyl)-N-((S)-1- 3.86 (m, 1H), 4.03 (m, 3H), 6.94 (m, 1H),(methylamino)propan-2- 7.07-7.23 (m, 5H), 7.31 (m, 1H), 7.71 (m, 1H)yl)piperidine-1-carboxamide I-144A (3R)-3-((S)-1-hydroxy-5-methoxy-1- 331.36 488 0.98 (d, 3H), 1.01 (d, 3H), 2.42 (s, 3H),(2-methylbenzofuran-7-yl)pentyl)- 3.72 (s, 3H), 3.20 (s, 3H), 3.96 (brd, 1H), N-((S)-4-methyl-1- 4.08 (m, 1H), 4.39 (br, d), 6.43 (s, 1H),(methylamino)pentan-2- 7.14 (m, 1H), 7.30 (d, 1H), 7.37 (d, 1H)yl)piperidine-1-carboxamide I-145A (3R)-3-((S)-1-hydroxy-1-(2- 33 1.47488 0.98 (m, 6H), 1.24 (d, 3H), 2.70 (s, 3H),isobutylbenzofuran-7-yl)-5- 3.20 (s, 3H), 0.93 (br d, 1H), 4.10 (m,methoxypentyl)-N-((S)-1- 1H), 4.40 (br d, 1H), 6.43 (s, 1H),(methylamino)propan-2- 7.14 (m, 1H), 7.32 (d, 1H), 7.38 (d, 1H)yl)piperidine-1-carboxamide I-146A N-((S)-3-cyclohexyl-1- 33 1.59 4887.41 (t, 2H), 7.34-7.28 (m, 2H), (methylamino)propan-2-yl)-3-(1-7.24-7.18 (m, 1H), 4.16-3.96 (m, 2H), 3.80 (t,hydroxy-5-methoxy-1-phenylpentyl)- 1H), 3.26 (s, 3H), 2.25 (m, 1H).3-methylpiperidine-1-carboxamide I-147A (3R)-3-(1-(2- 33 1.49 490 7.36(m), 7.10 (m), 6.80 (m), 3.19 (m), (cyclopentylmethoxy)phenyl)-1- 3.11(s), 2.59 (s), 2.51 (s). hydroxy-5-methoxypentyl)-N-((S)-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-148A(3S)-N-((S)-3-cyclohexyl-1- 37 1.79 490 6.93-6.78 (m, 3H), 4.07-4.00 (m,2H), (methylamino)propan-2-yl)-3-((R)-1- 3.78 (d, J = 13.5 Hz, 1H), 3.19(t, J = 6.4 Hz, (2-fluoro-5-methylphenyl)-5- 2H), 3.15 (s, 3H), 2.96(dd, J = 12.4, methoxypentyl)piperidine-1- 3.4 Hz, 1H), 2.81 (dd, J =12.6, 10.2 Hz, carboxamide 1H), 2.71-2.59 (m, 2H), 2.61 (s, 3H), 2.20(s, 3H), 1.82-0.79 (m, 25H). I-149A (3R)-3-((S)-1-(benzo[b]thiophen-7-33 1.47 490 7.72 (d, 1H), 7.49 (d, 1H), 7.36-7.26 (m,yl)-1-hydroxy-5-methoxypentyl)- 3H), 4.36 (d, 1H), 4.09 (m, 1H), 3.93(d, N-((S)-4-methyl-1- 1H), 3.25 (t, 2H), 3.20 (s, 3H), 3.07 (dd,(methylamino)pentan-2- 1H), 2.93 (dd, 1H), 2.71 (s, 3H), 1.75 (m,yl)piperidine-1-carboxamide 1H), 0.97 (dd, 6H). I-151A^(b)(3R)-N-((S)-3-cyclohexyl-1- 33 492.3 2.33 (m, 1H), 2.66 (m, 2H), 2.77(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 2.95 (m, 1H), 3.28 (s, 3H),4.20 (m, 2H), (2-fluorophenyl)-1-hydroxy-5- 5.94 (m, 1H), 6.96 (m, 1H),methoxypentyl)piperidine-1- 7.13 (t, 1H), 7.24 (m, 1H), 7.56 (dd, 1H),carboxamide 8.87 (brs, 1H), 9.83 (brs, 1H) I-152A^(b)(3R)-3-((R)-(3-ethoxypropoxy)(3- 33 492 1.15 (m, 3H), 1.80 (t, 2H), 3.77(d, 1H), fluorophenyl)methyl)-N-((S)-3- 3.91 (d, 1H), 4.06 (d, 1H), 4.20(s, 1H), cyclohexyl-1-(methylamino)propan- 5.65 (s, 1H), 6.97 (m, 3H),7.30 (m, 1H), 2-yl)piperidine-1-carboxamide 8.70 (brs, 1H), 9.59 (brs,1H) I-153A (3R)-N-((S)-1-amino-3- 33 1.53 494, 7.32 (m, 1H), 7.22-7.10(m, 3H), 4.20 (d, cyclohexylpropan-2-yl)-3-((S)-1-(3- 496 J = 12.9 Hz,1H), 3.99-3.92 (m, 1H), chlorophenyl)-1-hydroxy-5- 3.86 (d, J = 13.2 Hz,1H), 3.15 (s, 3H), methoxypentyl)piperidine-1- 2.91 (dd, J = 12.7, 3.4Hz, 1H), 2.74 (dd, J = 12.4, carboxamide 9.8 Hz, 1H), 2.48-2.40 (m, 2H),1.92-0.74 (m, 24H). I-154A (3R)-3-((R)-(3-ethoxypropoxy)(3- 33 1.73 4947.36-7.29 (m, 3H), 7.20 (dd, 1H), 4.27 (d,chlorophenyl)methyl)-N-((S)-1- 1H), 4.03 (m, 1H), 3.00 (dd, 1H),amino-3-cyclohexylpropan-2- 2.84-2.74 (m, 2H), 1.12 (t, 3H), 1.02 (m,1H), yl)piperidine-1-carboxamide 0.93 (m, 1H) I-155A(3R)-3-((S)-1-(3-chlorophenyl)-1,5- 134 1.4 494, 7.33-7.32 (m, 1H),7.21-7.09 (m, 3H), dihydroxypentyl)-N-((S)-3- 496 4.19 (d, J = 11.7 Hz,1H), 4.06-3.98 (m, cyclohexyl-1-(methylamino)propan- 1H), 3.86 (d, J =12.9 Hz, 1H), 3.37 (t, J = 6.6 Hz, 2-yl)piperidine-1-carboxamide 2H),2.95 (dd, J = 12.6, 3.2 Hz, 1H), 2.83 (dd, J = 12.6, 10.0 Hz, 1H), 2.59(s, 3H), 2.47-2.41 (m, 2H), 1.92-0.74 (m, 24H). I-156A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 119 1.56 495 1.40-1.75 (m, 9H), 3.20(s, 3H), 2.20 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-3- 7.10-7.80 (m,4H) cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamideI-157A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 495.3 2.51 (s, 3H), 2.72 (s,3H), 3.32 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.40 (m, 2H),3.70 (m, 1H), 4.26 (m, 2H), hydroxy-5-methoxy-1-(5- 5.88 (m, 1H), 7.61(m, 1H), 8.48 (brs, 1H), methylthiazol-2-yl)pentyl)piperidine- 9.27(brs, 1H) 1-carboxamide I-158A^(b) (3R)-3-((S)-1-(3-chlorophenyl)-1- 331.9 496 3.25 (s, 3H), 3.80 (m, 1H), 4.18 (d, 1H),hydroxy-5-methoxypentyl)-N-((S)-3- 4.50 (d, 1H), 7.00-7.40 (m, 5H)cyclohexyl-1-hydroxypropan-2- yl)piperidine-1-carboxamide I-159A(3R)-3-((3-methoxypropoxy)(4- 33 1.52 486 8.47 (d, J = 4.7, 1H), 8.12(d, 9.4, 0.5H), chloropyridin-2-yl)methyl)-N-((S)-3- 7.52 (s, 1H), 7.44(m, 1H), 6.89 (d, J = 9.4, cyclohexyl-1-(methylamino)propan- 0.5H), 4.27(d, J = 5.5, 0.5H), 2-yl)piperidine-1-carboxamide 4.15 (d, J = 7.4,0.5H), 3.29 (s, 3H), 2.68 (s, 3H) I-160A(R)-3-((S)-1-hydroxy-5-methoxy-1- 33 1.47 498 0.96 (m), 1.18-1.60 (m),1.26 (s), (2-phenoxyphenyl)pentyl)-N-(2- 1.88 (m), 2.22 (m), 2.36 (m),2.64 (s), 2.72 (m), methyl-1-(methylamino)propan-2- 3.14 (m), 3.24 (s),3.26 (t), 3.84 (d), yl)piperidine-1-carboxamide 4.38 (d), 6.78 (d), 6.94(d), 7.10 (m), 7.20 (m), 7.36 (m), 7.64 (d) I-161A(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)- 33 1.48 498 0.96 (m), 1.18 (d),1.20-1.64 (m), 1-hydroxy-5-methoxypentyl)-N-((S)- 1.94 (m), 2.22 (s),2.38 (m), 2.62 (s), 2.80 (m), 1-(methylamino)propan-2- 2.94 (dd), 3.04(dd), 3.24 (s), 3.26 (t), yl)piperidine-1-carboxamide 3.90 (d), 4.02(m), 4.38 (d), 6.54 (d), 6.74 (d), 7.04 (m), 7.16 (m), 7.28 (d), 7.64(d) I-162A (3R)-3-((S)-1-(2-(m- 33 1.47 498 0.96 (m), 1.20 (d),1.22-1.60 (m), tolyloxy)phenyl)-1-hydroxy-5- 1.92 (m), 2.22 (m), 2.26(s), 2.62 (m), 2.64 (s), methoxypentyl)-N-((S)-1- 2.78 (m), 2.96 (dd),3.04 (dd), 3.24 (s), (methylamino)propan-2- 3.26 (t), 3.86 (d), 4.04(m), 4.36 (d), yl)piperidine-1-carboxamide 6.72 (m), 6.76 (d), 6.92 (d),7.08 (m), 7.18 (m), 7.64 (d) I-163A(3R)-N-(3-(3,3-difluorocyclobutyl)-1- 33 1.37 500 7.32 (m, 1H), 7.15 (d,J = 7.0, 2H), (methylamino)propan-2-yl)-3-((S)-1- 6.94 (m, 1H), 4.42 (d,J = 12.5, 0.5H), 4.30 (d, (3-fluorophenyl)-1-hydroxy-5- J = 13.6, 0.5H),3.99 (m, 1H), 3.94 (d, J = 16, methoxypentyl)piperidine-1- 0.5H), 3.84(d, J = 12.9, 0.5H), carboxamide 3.30 (s, 3H), 2.70 (s, 1H) I-165A(3R)-3-((S)-1-(benzofuran-7-yl)-1- 119 500.3 0.72 (m, 1H), 2.26 (m, 1H),2.42 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-3- 2.60 (m, 1H), 2.72 (s,3H), 2.78 (m, 1H), cyclopentyl-1-(methylamino)propan- 2.94 (m, 1H), 3.09(m, 1H), 3.18 (s, 3H), 2-yl)piperidine-1-carboxamide 4.01 (m, 2H), 4.42(m, 1H), 6.84 (m, 1H), 7.22 (t, 1H), 7.41 (m, 1H), 7.51 (m, 1H), 7.67(m, 1H) I-166A (3R)-3-((S)-1-(3-chloro-2- 33 1.51 500 7.42 (t), 7.26(t), 7.03 (t), 4.24 (d), fluorophenyl)-1-hydroxy-5- 4.09 (m), 3.89 (d),3.19 (m), 3.15 (m), 2.93 (d), methoxypentyl)-N-((S)-4,4-dimethyl- 2.83(t), 2.68 (t), 2.60 (s), 2.51 (t), 2.05 (t), 1-(methylamino)pentan-2-1.86 (m), 0.89 (s). yl)piperidine-1-carboxamide I-167A3-(1-(3-chlorophenyl)-1-hydroxy-5- 129 1.55 501, 8.30 (d, J = 8.5 Hz,1H), 7.91-7.07 (m, methoxypentyl)-N-((S)-3-cyclohexyl- 503 8H),4.43-4.40 (m, 1H), 3.26 (t, J = 6.3 Hz, 1-(methylamino)propan-2- 2H),3.17 (s, 3H), 3.09-2.93 (m, 2H), yl)benzamide 2.61 (s, 3H), 2.27-2.22(m, 2H), 1.76-0.80 (m, 17H). I-168A (3R)-3-((S)-1-(2-(4- 33 1.42 5020.92 (m), 1.18 (d), 1.20-1.62 (m), fluorophenoxy)phenyl)-1-hydroxy-5-1.92 (m), 2.20 (m), 2.32 (m), 2.64 (s), 2.78 (m),methoxypentyl)-N-((S)-1- 2.96 (dd), 3.04 (dd), 3.24 (s), 3.26 (t),(methylamino)propan-2- 3.86 (d), 4.04 (m), 4.38 (d), 6.74 (d),yl)piperidine-1-carboxamide 6.94 (dd), 7.08 (m), 7.38 (m), 7.44 (dd)I-169A (3R)-3-((S)-1-(5-fluoro-2- 33 1.44 502 0.92 (m), 1.18 (d),1.20-1.62 (m), phenoxyphenyl)-1-hydroxy-5- 1.90 (m), 2.20 (m), 2.28 (m),2.64 (s), 2.76 (m), methoxypentyl)-N-((S)-1- 2.96 (m), 3.04 (dd), 3.24(s), 3.26 (t), (methylamino)propan-2- 3.86 (d), 4.04 (m), 4.36 (d), 6.80(dd), yl)piperidine-1-carboxamide 6.92 (m), 7.08 (m), 7.36 (m), 7.40(dd) I-170A (3R)-3-((S)-1-(2-(3- 33 1.45 502 0.84 (m), 1.18 (d),1.24-1.60 (m), fluorophenoxy)phenyl)-1-hydroxy-5- 1.92 (m), 2.16 (m),2.24 (m), 2.62 (m), 2.64 (s), methoxypentyl)-N-((S)-1- 2.78 (dd), 2.96(dd), 3.04 (dd), 3.24 (s), (methylamino)propan-2- 3.26 (t), 3.86 (d),4.04 (m), 4.36 (d), yl)piperidine-1-carboxamide 6.64 (d), 6.74 (d), 6.84(m), 7.18 (m), 7.24 (m), 7.34 (m), 7.68 (d) I-171A (3R)-3-((S)-1-(2-(2-33 1.44 502 7.66 (d, 1H), 7.27-7.23 (m, 1H),fluorophenoxy)phenyl)-1-hydroxy-5- 7.19-7.12 (m, 3H), 7.08 (t, 1H), 7.01(m, 1H), methoxypentyl)-N-((S)-1- 6.62 (d, 1H), 4.42 (dd, 1H), 4.05 (m,1H), (methylamino)propan-2- 3.86 (dd, 1H), 3.72 (m, 2H), 2.67 (d, 3H),yl)piperidine-1-carboxamide 1.93 (td, 1H). I-172A(3R)-N-((S)-3-cyclopentyl-1- 122 502.3 1.95 (m, 1H), 2.10 (m, 1H), 2.26(m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 2.72 (s, 3H), 3.26 (s, 3H),4.02 (m, 2H), (2,3-dihydrobenzofuran-7-yl)-1- 4.28 (m, 1H), 4.49 (m,2H), 6.83 (m, 2H), hydroxy-5- 7.11 (m, 1H), 7.21 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-173A^(b)(3R)-N-((S)-3-cyclohexyl-1- 33 502.4 1.05 (m, 4H), 2.30 (s, 3H), 2.37(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 2.93 (m, 2H), 3.78 (d, 1H),4.10 (d, 1H), hydroxy-5-methoxy-1-(2,5- 4.20 (m, 1H), 5.79 (m, 1H),dimethylphenyl)pentyl)piperidine-1- 8.72 (brs, 1H), 10.06 (brs, 1H)carboxamide I-174A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33 502..4 2.31 (dd,1H), 2.32 (s, 3H), 3.32 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1-4.22 (m, 2H), 5.90 (m, 1H), 8.96 (brs, 1H), (3-ethylphenyl)-1-hydroxy-5-9.97 (brs, 1H) methoxypentyl)piperidine-1- carboxamide I-175A^(b)(3R)-N-((S)-3-cyclohexyl-1- 33 502.4 2.26 (s, 3H), 2.29 (s, 3H), 3.26(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 4.18 (m, 2H), 5.72 (m, 1H),7.05 (d, 2H), hydroxy-5-methoxy-1-(2,3- 7.34 (m, 1H), 8.72 (brs, 1H),9.99 (brs, 1H) dimethylphenyl)pentyl)piperidine-1- carboxamideI-176A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 502 1.54 (dd, 1H), 2.30 (s,3H), 2.55 (t, 1H), (methylamino)propan-2-yl)-3-((S)-1- 3.27 (s, 3H),3.32 (t, 3H), 3.76 (m, 1H), hydroxy-5-methoxy-1-(3,5- 4.26 (m, 2H), 5.95(m, 1H), 6.86 (s, 1H), dimethylphenyl)pentyl)piperidine-1- 6.91 (s, 2H),8.67 (brs, 1H), 9.54 (brs, 1H) carboxamide I-177A (3R)-3-((S)-1-(2-(2-121 502.2 1.02 (m, 1H), 1.15 (d, 3H), 1.76 (m, 2H),chlorophenyl)phenyl)-1-hydroxy-5- 2.60 (m, 1H), 2.69 (m, 2H), 2.72 (m,1H), methoxypentyl)-N-((S)-1- 3.00 (m, 2H), 3.26 (m, 3H), 3.37 (m, 1H),(methylamino)propan-2- 3.82-4.13 (m, 3H), 6.94 (m, 1H),yl)piperidine-1-carboxamide 7.16-7.48 (m, 6H), 7.69 (m, 1H) I-178A(3R)-3-((S)-1-(2-(4- 121 502.3 0.99 (m, 1H), 1.18 (d, 3H), 1.85 (m, 1H),chlorophenyl)phenyl)-1-hydroxy-5- 2.59 (m, 1H), 2.68 (s, 3H), 2.75 (m,1H), methoxypentyl)-N-((S)-1- 2.94 (m, 1H), 3.04 (m, 1H), 3.25 (m, 3H),(methylamino)propan-2- 3.88 (m, 1H), 4.05 (m, 2H), 6.94 (m, 1H),yl)piperidine-1-carboxamide 7.05-7.50 (m, 6H), 7.72 (m, 1H) I-179A^(b)(3R)-N-((S)-3-cyclohexyl-1- 33 504.4 2.15 (m, 2H), 2.54 (dd, 1H), 3.26(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.80 (s, 3H), 4.20 (m, 2H),6.04 (m, 1H), hydroxy-5-methoxy-1-(3- 6.75 (d, 1H), 6.77 (t, 2H), 7.24(d, 1H), methoxyphenyl)pentyl)piperidine-1- 9.18 (brs, 1H), 9.86 (brs,1H) carboxamide I-180A (3R)-3-(1-(2- 33 1.56 504 7.41 (m), 7.35 (m),7.08 (q), 6.78 (m), (cyclopropylmethoxy)phenyl)-1- 4.15 (m), 3.91 (brm), 3.71 (m), 3.19 (m), hydroxy-5-methoxypentyl)-N-((S)-4- 3.12 (s),2.59 (s), 2.51 (s), 0.50 (t), methyl-1-(methylamino)pentan-2- 0.22 (m).yl)piperidine-1-carboxamide I-181A (3R)-3-(1-(3-chlorophenyl)-4- 33 1.87504 7.32 (s), 7.22-7.11 (m), 4.17 (d), 4.00 (m),cyclopropyl-1-hydroxybutyl)-N-((S)- 3.86 (d), 3.18 (m), 2.94 (d), 2.79(t), 3-cyclohexyl-1- 2.58 (s), 2.41 (q), 0.49 (m), 0.24 (m), −0.18 (q).(methylamino)propan-2- yl)piperidine-1-carboxamide I-182A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 506 1.57 (dd, 1H), 2.04 (t, 1H), 2.21(m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 2.82 (s, 3H), 2.55 (t, 1H),2.82 (s, 3H), (3-fluoro-5-methylphenyl)-1- 3.28 (s, 3H), 4.25 (m, 2H),6.05 (m, 1H), hydroxy-5- 6.74 (d, 1H), 6.86 (m, 2H), 8.99 (brs, 1H),methoxypentyl)piperidine-1- 9.74 (brs, 1H) carboxamide I-183A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 506.4 2.32 (s, 3H), 2.76 (s, 3H), 3.27(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.33 (m, 2H), 4.13 (m, 1H),4.26 (m, 1H), (2-fluoro-5-methylphenyl)-1- 5.96 (m, 1H), 6.84 (t, 1H),6.87 (m, 1H), hydroxy-5- 7.31 (d, 1H), 8.75 (brs, 1H), 9.67 (brs, 1H)methoxypentyl)piperidine-1- carboxamide I-184A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 506.4 2.22 (m, 1H), 2.35 (s, 3H), 2.67(m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 2.73 (s, 3H), 2.93 (m, 2H),3.26 (s, 3H), (5-fluoro-2-methylphenyl)-1- 3.78 (m, 1H), 4.12 (m, 1H),4.23 (m, 1H), hydroxy-5- 5.98 (m, 1H), 6.80 (m, 1H), 7.02 (m, 1H),methoxypentyl)piperidine-1- 7.31 (m, 1H), 8.87 (brs, 1H), 9.84 (brs, 1H)carboxamide I-185A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 506.3 2.24 (s,3H), 2.45 (t, 1H), 2.63 (m, 2H), (methylamino)propan-2-yl)-3-((S)-1-2.79 (s, 3H), 2.92 (m, 1H), 3.28 (s, 3H), (2-fluoro-3-methylphenyl)-1-3.76 (m, 1H), 4.14 (m, 1H), 4.26 (m, 1H), hydroxy-5- 5.99 (m, 1H), 7.00(t, 1H), 7.09 (t, 1H), methoxypentyl)piperidine-1- 7.43 (t, 1H), 8.88(brs, 1H), 9.89 (brs, 1H) carboxamide I-186A(3R)-N-((2R)-1-cyclohexyl-1- 117 1.44 508 0.98 (m), 1.18-2.06 (m), 2.60(m), hydroxy-3-(methylamino)propan-2- 2.74 (s), 3.14 (dd), 3.22 (dd),3.24 (s), yl)-3-((S)-1-(3-fluorophenyl)-1- 3.28 (tm), 4.00 (d), 4.24(m), 6.94 (m), hydroxy-5- 7.16 (m), 7.36 (m) methoxypentyl)piperidine-1-carboxamide I-186B (3R)-N-((1S,2R)-1-cyclohexyl-1- 117 1.38 5080.98-2.02 (m), 2.54 (m), 2.72 (s), hydroxy-3-(methylamino)propan-2- 3.04(m), 3.24 (s), 3.26 (t), 3.42 (m), 3.84,yl)-3-((S)-1-(3-fluorophenyl)-1- 3.98 (d), 4.08 (m), 4.26, 4.42 (d),6.96 (m), hydroxy-5- 7.18 (m), 7.34 (m) methoxypentyl)piperidine-1-carboxamide I-187A (3R)-3-((S)-1-(3-fluorophenyl)-1- 114 1.37 508 7.32(q, 1H), 7.16 (m, 1H), 7.14 (m, 1H), hydroxy-5-methoxypentyl)-N-(3-(1-6.94 (m, 1H), 4.42 and 4.28 (two isomers hydroxycyclohexyl)-1- on 3 to 2ratio, d, 1H), 4.15 (m, 1H), (methylamino)propan-2- 3.95 and 3.84 (twoisomers on 3 to 2 ratio, d, yl)piperidine-1-carboxamide 1H), 3.32 (m,1H), 3.26 (s, 3H), 3.14 (dd, 1H), 2.95 (m, 1H), 2.70 (s, 3H), 2.60-2.39(m 3H), 1.94 (t, 2H), 1.79-1.22 (m, 20H), 1.00 (m, 1H). I-188A(3R)-3-((S)-1-(3-fluorophenyl)-1- 115 1.34 508 7.32 (t, 1H), 7.16 (d,1H), 7.14 (d, 1H), hydroxy-5-methoxypentyl)-N-(3-(1- 6.94 (td, 1H), 4.36(t, 1H), 3.88 (t, 1H), hydroxycyclohexyl)-2- 3.53 (m, 1H), 3.40 (m, 1H),3.26 (s, 3H), (methylamino)propyl)piperidine-1- 2.61 (s, 3H), 2.48 (m,1H), 2.47 (m, 1H), carboxamide 1.94 (t, 2H), 1.90 (td, 1H), 1.76 (tt,1H), 1.69-1.22 (m, 18H), 0.99 (m, 1H). I-190A(3R)-3-((R)-(3-ethoxypropoxy)(3- 33 1.75 508 7.36-7.29 (m, 3H), 7.25 (d,1H), 4.28 (d, chlorophenyl)methyl)-N-((S)-3- 1H), 4.10 (m, 1H), 3.05(dd, 2H), 2.90 (m, cyclohexyl-1-(methylamino)propan- 1H), 2.69 (s, 3H),1.12 (t, 3H). 2-yl)piperidine-1-carboxamide I-191A(3R)-3-((1S)-1-(3-chlorophenyl)-1,5- 136 1.53 508, 7.36-7.34 (m, 1H),7.24-7.13 (m, 3H), dihydroxyhexyl)-N-((S)-3- 510 4.20 (d, J = 15 Hz,1H), 4.06-3.99 (m, cyclohexyl-1-(methylamino)propan- 1H), 3.88 (d, J =13.2 Hz, 1H), 2-yl)piperidine-1-carboxamide 3.58-3.53 (m, 1H), 2.97 (dd,J = 12.8, 3.1 Hz, 1H), 2.82 (dd, J = 12.6, 10.2 Hz, 1H), 2.61 (s, 3H),2.49-2.41 (m, 2H), 0.987, 0.982 (d, J = 6 Hz, 3H), 1.94-0.80 (m, 24H).I-192A^(b) (3R)-3-((S)-1-(2-chlorophenyl)-1- 121 508.3 1.54 (m, 2H),2.97 (m, 1H), 3.26 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-3- 3.82 (m,1H), 4.06 (m, 1H), 4.28 (m, 1H), cyclohexyl-1-(methylamino)propan- 5.91(m, 1H), 7.18&7.30 (m, 3H), 2-yl)piperidine-1-carboxamide 7.75 (m, 1H),8.28 (brs, 1H), 9.66 (brs, 1H) I-193A(3R)-3-((S)-1-(4-chloropyridin-2-yl)- 33 1.44 510 8.51 (d, J = 5.8, 1H),8.12 (d, J = 9.0, 1-hydroxy-5-methoxypentyl)-N-((S)- 0.5H), 7.81 (bs,1H), 7.52 (bs, 1H), 3-cyclohexyl-1- 6.88 (d, J = 9.0, 0.5H), 4.35 (d, J= 12.1, 1H), (methylamino)propan-2- 4.12 (m, 1H), 3.94 (d, J = 12.1,1H), yl)piperidine-1-carboxamide 3.29 (s, 3H), 2.70 (s, 3H) I-194A^(b)(3R)-3-((R)-(3- 33 510.3 1.14 (t, 3H), 2.71 (s, 3H), 3.79 (m, 1H),ethoxypropoxy)(phenyl)methyl)- 3.93 (dd, 1H), 5.78 (m, 1H), 7.20 (m,2H), N-((S)-3-(4,4-difluorocyclohexyl)-1- 7.34 (m, 3H), 8.77 (brs, 1H),9.87 (brs, 1H) (methylamino)propan-2- yl)piperidine-1-carboxamideI-195A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33 510 1.52 (m, 1H), 2.04 (t,1H), 2.18 (m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 2.58 (t, 1H),2.81 (s, 3H), 2.88 (m, 1H), (3,5-difluorophenyl)-1-hydroxy-5- 3.28 (s,3H), 3.30 (t, 3H), 3.71 (m, 1H), methoxypentyl)piperidine-1- 4.25 (m,2H), 6.04 (m, 1H), 6.68 (dd, 1H), carboxamide 6.87 (d, 2H), 8.96 (brs,1H), 9.65 (brs, 1H) I-196A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 510 2.41(m, 1H), 2.64 (s, 3H), 3.22 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1-3.77 (m, 1H), 4.13 (m, 1H), 4.28 (m, 1H),(2,3-difluorophenyl)-1-hydroxy-5- 6.02 (m, 1H), 7.05 (m, 2H), 7.30 (m,1H), methoxypentyl)piperidine-1- 8.81 (brs, 1H), 9.49 (brs, 1H)carboxamide I-197A^(b) (3R)-N-((S)-3-cyclopentyl-1- 119 510.6 1.24 (t,3H), 2.42 (m, 2H), 2.65 (t, 1H), (methylamino)propan-2-yl)-3-((S)-5-2.71 (s, 3H), 2.94 (m, 2H), 3.26 (m, 1H),ethoxy-1-(2,3-difluorophenyl)-1- 3.35 (t, 2H), 3.45 (m, 2H), 3.72 (m,1H), hydroxypentyl)piperidine-1- 4.19 (m, 1H), 6.15 (m, 1H), 7.06 (m,2H), carboxamide 7.31 (t, 1H), 9.10 (brs, 1H), 10.13 (brs, 1H) I-198A(3R)-N-((S)-3-cyclohexyl-1- 33 1.44 510 7.24 (m), 7.01 (m), 4.21 (d),4.01 (m), (methylamino)propan-2-yl)-3-((S)-1- 3.87 (d), 3.18 (s), 3.13(s), 2.95 (d) (2,3-difluorophenyl)-1-hydroxy-5- 2.80 (t), 2.69 (t), 2.58(s), 2.51 (t). methoxypentyl)piperidine-1- carboxamide I-199A^(b)(3R)-3-((S)-1-(2-phenylphenyl)-1- 119 510.3 0.89 (t, 6H), 2.71 (m, 4H),3.15 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-4- 3.28 (s, 3H), 3.30 (m,2H), 3.75 (m, 1H), methyl-1-(methylamino)pentan-2- 3.93 (m, 1H), 4.12(m, 1H), 5.58 (m, 1H), yl)piperidine-1-carboxamide 7.00 (d, 1H), 7.21(m, 3H), 7.34 (m, 5H), 8.62 (brs, 1H), 9.86 (brs, 1H) I-200A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.3 511 2.40 (s, 3H), 3.20 (s, 3H),3.2-3.3 (m, 4H), hydroxy-5-methoxypentyl)-N-((S)-3- 3.80 (m, 1H),7.10-7.40 (m, 4H) (tetrahydro-2H-pyran-4-yl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-201A (2RS)-2-((RS)-1-(3-chlorophenyl)-1-33 1.5 510 2.26 (dd), 2.42 (dd), 2.67 (s), 3.52 (m),hydroxy-5-methoxypentyl)-N-((S)-3- 3.66 (br d), 3.80 (br d), 3.92 (m),cyclohexyl-1-(methylamino)propan- 4.12 (m), 7.2-7.62-yl)morpholine-4-carboxamide I-202A (3R)-N-((1R,2R)-3-amino-1- 117 1.50510 1.00 (m), 1.18-2.08 (m), 2.42 (m),cyclohexyl-1-hydroxypropan-2-yl)-3- 2.62 (m), 3.10 (m), 3.26 (s), 3.28(t), 3.82, ((S)-1-(3-chlorophenyl)-1-hydroxy- 3.98 (d), 4.08 (m), 4.24,4.42 (d), 5-methoxypentyl)piperidine-1- 7.20-7.34 (m), 7.42 (s)carboxamide I-202B (3R)-N-((1S,2R)-3-amino-1- 117 1.48 510 1.00-2.00(m), 2.40-2.64 (m), 2.96 (m), cyclohexyl-1-hydroxypropan-2-yl)-3- 3.26(s), 3.28 (t), 3.42 (m), 3.84, 3.98 (d),((S)-1-(3-chlorophenyl)-1-hydroxy- 4.04 (m), 4.28, 4.42 (d), 7.22-7.36(m), 5-methoxypentyl)piperidine-1- 7.42 (s) carboxamide I-203A(3R)-3-((S)-1-(3-chlorophenyl)-1- 117 1.48 510 2.72 (s, 3H), 3.30 (s,3H), 3.95 (m, 1H), hydroxy-5-methoxypentyl)- 4.19 (m, 1H), 7.20-7.50 (m,4H) N-((1R,2R)-1-cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-203B (3R)-3-((S)-1-(3-chlorophenyl)-1- 1171.37 510 2.70 (s, 3H), 3.30 (s, 3H), 3.95 (m, 1H),hydroxy-5-methoxypentyl)- 4.25 (d, 1H), 7.20-7.50 (m, 4H)N-((1S,2R)-1-cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-204A (R)-3-((S)-1-(2-(o-tolyloxy)phenyl)-33 1.53 512 0.96 (m), 1.20-1.60 (m), 1.26, 1.28 (s),1-hydroxy-5-methoxypentyl)-N-(2- 1.92 (m), 2.24 (s), 2.40 (m), 2.64 (s),methyl-1-(methylamino)propan-2- 2.74 (m), 3.14 (dd), 3.24 (s), 3.26 (t),3.84 (d), yl)piperidine-1-carboxamide 4.42 (d), 6.58 (d), 6.76 (d), 7.04(m), 7.16 (m), 7.26 (d), 7.64 (d) I-205A (3R)-3-((S)-1-(2-(2- 33 1.55512 0.96 (m), 1.18 (d), 1.20 (t), 1.22-1.64 (m),ethylphenoxy)phenyl)-1-hydroxy-5- 1.96 (m), 2.40 (m), 2.64 (s), 2.82(dd), methoxypentyl)-N-((S)-1- 2.94 (dd), 3.02 (dd), 3.24 (s), 3.26 (t),(methylamino)propan-2- 3.94 (d), 4.02 (m), 4.38 (d), 6.56 (d),yl)piperidine-1-carboxamide 6.74 (d), 7.00-7.20 (m), 7.30 (d), 7.64 (d)I-206A (3R)-3-((S)-1-(3-chloro-2- 119 1.6 512 2.50 (s, 3H), 3.20 (s,3H), 6.80-7.50 (m, 4H) fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3- cyclopentyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide I-206B (3R)-3-((S)-1-(3-chloro-2- 119 1.63563 2.60 (s, 3H), 3.25 (s, 3H), 7.0-7.5 (m, 3H)fluorophenyl)-1-hydroxy-5- methoxypentyl)-N-((R)-3-cyclopentyl-1-(methylamino)propan- 2-yl)piperidine-1-carboxamideI-207A^(b) (3R)-3-((S)-1-(5-chloro-1-methyl- 121 512.3 2.26 (m, 3H),2.72 (s, 3H), 2.75 (m, 2H), 1H-imidazol-2-yl)-1-hydroxy-5- 3.01 (m, 1H),3.10 (m, 1H), 3.27 (s, 3H), methoxypentyl)-N-((S)-3-cyclohexyl- 3.34 (m,2H), 3.74 (m, 1H), 3.94 (s, 3H), 1-(methylamino)propan-2- 4.19 (m, 1H),4.32 (m, 1H), 6.03 (m, 1H), yl)piperidine-1-carboxamide 7.35 (m, 1H),8.84 (brs, 1H), 9.24 (brs, 1H) I-208A (3R)-3-((S)-1-(2,2- 33 1.52 5140.94 (d), 1.00 (d), 2.61 (m), 2.72 (s),difluorobenzo[d][1,3]dioxol-4-yl)-1- 2.92 (dd), 3.06 (dd), 3.15 (s),3.98 (br d), hydroxy-5-methoxypentyl)-N-((S)-4- 4.10 (m), 4.35 (br dd),7.13 (m), 7.30 (dd) methyl-1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-209A (R)-3-((S)-1-(3-chlorophenyl)-1- 121436 0.90 (m, 1H), 1.58 (s, 3H), 2.57 (m, 2H),hydroxyethyl)-N-((S)-1-cyclohexyl-3- 2.66 (s, 3H), 2.89 (m, 1H), 3.04(m, 1H), (methylamino)propan-2-yl)piperidine- 3.97 (d, 1H), 4.12 (m,1H), 4.24 (d, 1H), 1-carboxamide 7.24 (m, 1H), 7.32 (m, 2H), 7.46 (s,1H) I-210A (3R)-3-((S)-1-(benzofuran-7-yl)-1- 33 1.55 514 2.10 (m), 2.26(m), 2.44 (m), 2.60 (m), hydroxy-5-methoxypentyl)-N-((S)-3- 2.70 (s),2.82 (m), 2.93 (m), 3.19 (s), cyclohexyl-1-(methylamino)propan- 4.00 (brd), 4.15 (m), 4.39 (br d), 2-yl)piperidine-1-carboxamide 6.86 (s), 7.20(dd), 7.41 (d), 7.52 (d), 7.65 (s) I-211A (3R)-N-((S)-3-cyclohexyl-1-121 514.3 2.12 (m, 2H), 2.48 (m, 2H), 2.69 (s, 3H),(methylamino)propan-2-yl)-3-((R)-1- 2.90 (m, 1H), 3.08 (m, 1H), 2.37 (s,3H), hydroxy-1-(1H-indazol-7-yl)-5- 2.93 (m, 2H), 3.25 (s, 3H), 3.95 (m,1H), methoxypentyl)piperidine-1- 4.14 (m, 1H), 4.43 (m, 1H), 7.15 (m,2H), carboxamide 7.66 (m, 1H), 8.02 (m, 1H) I-212A^(b) (3R)-3-((R)-(3-119 516.5 2.69 (s, 3H), 2.75 (m, 1H), 2.96 (m, 1H), methoxypropoxy)(2,3-3.10 (m, 1H), 3.28 (s, 3H), 3.42 (m, 2H),dichlorophenyl)methyl)-N-((S)-3- 3.81 (m, 1H), 4.08 (m, 2H), 4.46 (m,1H), cyclopentyl-1-(methylamino)propan- 5.65 (m, 1H), 7.29 (m, 2H), 7.40(d, 1H), 2-yl)piperidine-1-carboxamide 8.62 (brs, 1H), 9.73 (brs, 1H)I-213A (R)-3-((S)-1-(2-(4- 33 1.49 516 0.96 (m), 1.20-1.60 (m), 1.32(s), fluorophenoxy)phenyl)-1-hydroxy-5- 1.88 (m), 2.20 (m), 2.36 (m),2.64 (s), methoxypentyl)-N-(2-methyl-1- 2.72 (m), 3.16 (dd), 3.24 (s),3.26 (t), (methylamino)propan-2- 3.82 (d), 4.38 (d), 6.74 (d), 6.96 (m),yl)piperidine-1-carboxamide 7.08 (m), 7.20 (m), 7.64 (d) I-214A(R)-3-((S)-1-(2-(3- 33 1.49 516 0.96 (m), 1.12-1.60 (m), 1.32 (s),fluorophenoxy)phenyl)-1-hydroxy-5- 1.88 (m), 2.10 (m), 2.24 (m), 2.64(s), methoxypentyl)-N-(2-methyl-1- 2.72 (m), 3.16 (dd), 3.24 (s), 3.26(t), (methylamino)propan-2- 3.82 (d), 4.38 (d), 6.64 (dd), 6.74 (dd),yl)piperidine-1-carboxamide 6.82 (m), 6.84 (d), 7.18 (m), 7.24 (m), 7.34(m), 7.68 (dd) I-215A (3R)-3-((S)-1-(3-(o-tolyloxy)-2- 33 1.52 516 1.10(2s, 3H), 2.25 (s, 3H), 3.30 (s, 3H), fluorophenyl)-1-hydroxy-5- 4.10(m, 1H), 6.65 (d, 1H), 6.85 (t, 1H), methoxypentyl)-N-((S)-1- 7.00 (t,1H), 7.10 (m, 2H), 7.25 (d, 1H), (methylamino)propan-2- 7.39 (t, 1H)yl)piperidine-1-carboxamide I-216A (3R)-3-((S)-1-(2-(o-tolyloxy)-3- 331.44 516 0.70-1.00 (m), 1.18, 1.22 (two d), fluorophenyl)-1-hydroxy-5-1.28-1.78 (m), 1.92 (m), 2.36, 2.38 (two s), methoxypentyl)-N-((S)-1-2.52 (m), 2.62, 2.70 (two s), 2.78 (m), (methylamino)propan-2- 2.92,3.02 (m), 3.04, 3.36 (two t), 3.18, yl)piperidine-1-carboxamide 3.24(two s), 3.76, 3.98 (d), 3.96, 4.08 (m), 4.30 (d), 6.40, 6.42 (two d),6.90 (m), 7.00 (m), 7.12 (m), 7.22 (m), 7.56 (d) I-217A(3R)-3-((S)-1-(2-(5-fluoro-2- 33 1.48 516 0.94 (m), 1.20 (d), 1.22-1.64(m), methylphenoxy)phenyl)-1-hydroxy- 1.94 (m), 2.22 (s), 2.30 (m), 2.64(s), 5-methoxypentyl)-N-((S)-1- 2.80 (dd), 2.99 (dd), 3.04 (dd), 3.24(s), (methylamino)propan-2- 3.26 (t), 3.92 (d), 4.04 (m), 4.38 (d), 6.44(d), yl)piperidine-1-carboxamide 6.66 (d), 6.80 (m), 7.14 (m), 7.22 (m),7.26 (m), 7.68 (d) I-218A (3R)-3-((S)-1-(2-(4-fluoro-2- 33 1.49 516 0.94(m), 1.18 (d), 1.22-1.64 (m), methylphenoxy)phenyl)-1-hydroxy- 1.94 (m),2.22 (s), 2.38 (m), 2.64 (s), 5-methoxypentyl)-N-((S)-1- 2.80 (dd), 2.98(m), 3.04 (m), 3.24 (s), (methylamino)propan-2- 3.26 (t), 3.92 (d), 4.04(m), 4.40 (d), 6.46 (d), yl)piperidine-1-carboxamide 6.74 (m), 6.92 (m),7.06 (m), 7.16 (m), 7.62 (d) I-219A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121516.3 2.93 (m, 1H), 315 (m, 1H), 3.28 (s, 3H),(methylamino)propan-2-yl)-3-((S)-1- 3.34 (m, 1H), 3.88 (m, 1H), 4.25 (m,1H), (2,3-dihydrobenzofuran-7-yl)-1- 4.54 (t, 2H), 5.85 (m, 1H), 6.84(m, 1H), hydroxy-5- 7.11 (m, 2H), 8.51 (brs, 1H), 9.12 (brs, 1H)methoxypentyl)piperidine-1- carboxamide I-220A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.5 517 7.26 (m, 4H), 4.64 (d, J =20.2, 0.5H), hydroxy-5-methoxypentyl)-N-(3- 4.31 (d, 14.8, 0.5H), 4.01(m, 1H), (3,3-difluorocyclobutyl)-1- 3.94 (d, J = 12.1, 0.5H), 3.30 (s,3H), (methylamino)propan-2- 2.70 (2, 3H) yl)piperidine-1-carboxamideI-221A (3R)-N-(3-(3,3-difluorocyclobutyl)-1- 33 1.52 591 7.42 (d),7.19-7.11 (m), 7.05 (t), (methylamino)propan-2-yl)-3-((S)-1- 6.91 (m),6.70 (d), 4.33 (d), 4.14 (d) (2,3-difluorophenyl)-1-hydroxy-5- 3.88 (m),3.77 (d), 3.62 (d), 3.20 (m), methoxypentyl)piperidine-1- 3.13 (s), 2.58(s). carboxamide I-222A (3R)-3-(1-(2- 33 1.65 518 7.41 (m), 7.34 (m),7.06 (m), 6.75 (m), (cyclopentyloxy)phenyl)-1-hydroxy- 4.09, (d), 3.92(m), 3.75 (br s), 3.18 (br 5-methoxypentyl)-N-((S)-4-methyl- s), 3.12(s), 2.95 (m), 2.59 (s), 2.52 (s). 1-(methylamino)pentan-2-yl)piperidine-1-carboxamide I-223A (3R)-3-(1-(2-(2- 33 1.65 518 7.44(m), 7.35 (m), 7.10 (q), 6.82 (m), cyclopropylethoxy)phenyl)-1- 4.12(m), 3.93 (m), 3.75 (br s), 3.18 (br hydroxy-5-methoxypentyl)-N-((S)-4-s), 3.12 (s), 2.60 (s), 2.50 (s), 0.40 (m),methyl-1-(methylamino)pentan-2- 0.04 (m). yl)piperidine-1-carboxamideI-224A (3R)-3-((S)-1-(2-(2- 33 1.44 518 0.94 (m), 1.20 (d), 1.22-1.60(m), chlorophenoxy)phenyl)-1-hydroxy- 1.94 (m), 2.38 (m), 2.64 (s), 2.80(m), 5-methoxypentyl)-N-((S)-1- 2.94 (m), 3.04 (m), 3.24 (s), 3.26 (t),3.92 (d), (methylamino)propan-2- 4.04 (m), 4.38 (d), 6.60 (d), 6.94 (d),yl)piperidine-1-carboxamide 7.10-7.22 (m), 7.28 (m), 7.52 (d), 7.68 (d)I-225A (3R)-3-(1-hydroxy-5-methoxy-1-(2- 33 1.71 520 7.37 (br s), 7.08(m), 6.81 (m), 4.47 (m), (neopentyloxy)phenyl)pentyl)- 4.12 (m), 3.95(m), 3.67 (m), 3.54 (m), N-((S)-4-methyl-1- 3.19 (m), 3.12 (s, 2.60 (s),0.98 (s). (methylamino)pentan-2- yl)piperidine-1-carboxamide I-226A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 520.4 2.12 (m, 2H), 2.48 (s, 3H), 3.27(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.74 (m, 1H), 4.27 (m, 2H),6.09 (m, 1H), hydroxy-5-methoxy-1-(3- 7.06 (d, 1H), 7.11 (d, 1H), 7.24(m, 1H), (methylthio)phenyl)pentyl)piperidine- 7.28 (m, 1H), 9.18 (brs,1H), 9.87 (brs, 1H) 1-carboxamide I-227A(3R)-3-((S)-4-(acetylamino)-1-(3- 33 1.32 521, 7.30 (t, J = 1.8 Hz, 1H),7.20-7.08 (m, chlorophenyl)-1-hydroxybutyl)- 523 3H), 4.16 (d, J = 12.9Hz, 1H), N-((S)-3-cyclohexyl-1- 4.05-3.97 (m, 1H), 3.84 (d, J = 12.6 Hz,1H), (methylamino)propan-2- 2.99-2.91 (m, 3H), 2.81 (dd, J = 12.7,yl)piperidine-1-carboxamide 10.1 Hz, 1H), 2.57 (s, 3H), 2.45-2.37 (m,2H), 1.76 (s, 3H), 1.88-0.75 (m, 22H). I-228A (3R)-3-(1-(2-(allyloxy)-5-33 1.53 521 7.26 (d, J = 10.9, 1H), 6.88 (2H), fluorophenyl)-5-ethoxy-1-6.04 (m, 1H), 5.36 (d, J = 17.1, 1H), 5.23 (d,hydroxypentyl)-N-((S)-4-methyl-1- J = 10.5, 1H), 4.53 (bs, 1H), 4.26 (d,J = 13.3, (methylamino)pentan-2- 1H), 4.08 (m, 1H), 3.97 (d, J = 12.9,yl)piperidine-1-carboxamide 1H), 3.40 (q, J = 5.9, 2H), 2.70 (s, 3H),I-229A^(b) (3R)-N-((S)-3-cyclohexyl-1- 33 522.3 2.08 (m, 1H), 2.25 (m,1H), 2.75 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.28 (s, 3H),3.78 (s, 3H), 4.08 (m, 1H), (5-fluoro-2-methoxyphenyl)-1- 4.18 (m, 1H),5.69 (m, 1H), 6.77 (m, 1H), hydroxy-5- 6.89 (m, 1H), 7.15 (m, 1H), 8.75(brs, 1H), methoxypentyl)piperidine-1- 10.03 (brs, 1H) carboxamideI-230A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121 522 1.91 (m, 1H), 2.18 (m,1H), 3.14 (m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 3.27 (s, 3H),3.30 (t, 3H), 3.90 (s, 3H), (2-fluoro-6-methoxyphenyl)-1- 4.05 (m, 1H),4.16 (m, 1H), 5.66 (m, 1H), hydroxy-5- 6.72 (m, 2H), 7.20 (m, 1H), 8.74(brs, 1H), methoxypentyl)piperidine-1- 9.78 (brs, 1H) carboxamide I-231A(3R)-3-(4-cyclopropyl-1-hydroxy-1- 33 1.79 522 7.54 (d), 7.23 (t), 7.07(t), 6.99 (m), (2-phenoxyphenyl)butyl)-N-((S)-4- 6.80 (d), 6.61 (d),4.16 (d), 3.88 (m), methyl-1-(methylamino)pentan-2- 3.19 (m), 2.91 (d),2.76 (q), 2.54 (s), yl)piperidine-1-carboxamide 2.50 (m), 2.18 (q), 1.82(t), 0.72 (d), 0.66 (d), 0.45 (br m), 0.21 (d), −0.23 (br s). I-232A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.5 522 1.20 (m, 3H), 2.39 (2s,3H), 3.25 (s, 3H), hydroxy-5-methoxypentyl)-N-(5,5,5- 3.75 (m, 1H)7.10-7.20 (m, 4H) trifluoro-4-methyl-1- (methylamino)pentan-2-yl)piperidine-1-carboxamide I-233A^(b) (3R)-3-(1-(3-chlorophenyl)-1,5-33 1.78 522, 7.28-6.93 (m), 5.48 (t, J = 7.3 Hz),dimethoxypentyl)-N-((S)-3- 490, 4.79 (d, J = 7.6 Hz), 4.01-3.86 (m),3.27 (s), cyclohexyl-1-(methylamino)propan- 492 2.46 (s).2-yl)piperidine-1-carboxamide I-234A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.63 522 1.00 (t, 3H), 2.65 (m,2H), 3.27 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-3- 3.95 (m, 1H),7.10-7.30 (m, 4H) cyclohexyl-1-(ethylamino)propan-2-yl)piperidine-1-carboxamide I-235A (3R)-3-((1S)-1-(3-chlorophenyl)-1,5-137 1.59 522, 7.36-7.14 (m, 4H), 4.21 (d, J = 14.4 Hz,dihydroxyheptyl)-N-((S)-3- 524 1H), 4.07-4.01 (m, 1H), 3.89 (d, J = 11.6Hz, cyclohexyl-1-(methylamino)propan- 1H), 2.622, 2.607 (s, 3H).2-yl)piperidine-1-carboxamide I-236A^(b) (3R)-3-(4-cyclopropyl-1-(3- 331.68 524 9.77 (d), 8.98 (d), 7.29 (q), 7.08 (m),fluorophenyl)-1-hydroxybutyl)- 6.94 (m), 6.16 (br s), 5.12 (d), 4.23 (brN-((S)-3-(4,4-difluorocyclohexyl)-1- s), 3.73 (d), 3.30 (br s), 2.89(d), (methylamino)propan-2- 2.81 (s), 2.54 (t), 0.57 (m), 0.35 (d),yl)piperidine-1-carboxamide −0.06 (d). I-237A^(b) (3R)-N-((S)-3-(4,4-121 524.4 2.08 (m, 3H), 2.46 (s, 3H), 2.54 (t, 1H),difluorocyclohexyl)-1- 2.79 (s, 3H), 2.91 (m, 1H), 3.29 (s, 3H),(methylamino)propan-2-yl)-3-((S)-1- 3.76 (m, 1H), 4.24 (m, 2H), 6.13 (m,2H), hydroxy-5-methoxy-1-m- 7.06 (m, 3H), 7.22 (m, 1H), 8.87 (brs, 1H),tolylpentyl)piperidine-1- 9.78 (brs, 1H) carboxamide I-238A^(b)(3R)-3-((R)-(3-ethoxypropoxy)(m- 121 524.4 1.15 (t, 3H), 2.08 (m, 2H),2.37 (m, 6H), tolyl)methyl)-N-((S)-3-(4,4- 3.49 (m, 4H), 4.06 (m, 2H),4.51 (m, 2H), difluorocyclohexyl)-1- 7.10 (m, 4H) (methylamino)propan-2-yl)piperidine-1-carboxamide I-239A^(b) (R)-N-((S)-1-cyclohexyl-3- 119524.4 1.16 (t, 3H), 2.43 (m, 2H), 2.54 (t, 1H),(methylamino)propan-2-yl)-3-((S)-1- 2.81 (s, 3H), 2.94 (m, 2H), 3.27 (m,1H), (2,3-difluorophenyl)-5-ethoxy-1- 3.35 (t, 2H), 3.45 (m, 2H), 3.71(m, 1H), hydroxypentyl)piperidine-1- 4.20 (m, 2H), 6.15 (m, 1H), 7.04(m, 2H), carboxamide 7.31 (t, 1H), 9.13 (brs, 1H), 10.13 (brs, 1H)I-240A^(b) (3R)-3-((S)-1-(2-fluoro-3- 33 1.53 524 0.00 (m, 2H), 0.20 (m,1H), 0.4 (m, 2H), methylphenyl)-1-hydroxy-5- 2.40 (s, 3H), 3.20 (s, 3H),3.75 (m, 1H), methoxypentyl)-N-((S)-3-(cis-4- 6.75 (m, 1H), 6.90 (m,2H), 7.10 (m, 2H), fluorocyclohexyl)-1- 7.30 (m, 2H), 7.50 (m, 1H), 8.2(d, 1H) (methylamino)propan-2- yl)piperidine-1-carboxamide I-240B^(b)(3R)-N-((S)-3-cyclopropyl-1- 119 524.4 2.04 (m, 2H), 2.25 (s, 3H), 2.65(s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 2.79 (m, 1H), 3.01 (m, 1H),3.28 (s, 3H), hydroxy-5-methoxy-1-(2- 3.35 (m, 2H), 4.34 (m, 1H), 4.81(m, 1H), phenoxyphenyl)pentyl)piperidine-1- 7.04 (m, 1H), 7.07 (m, 1H),7.36 (m, 1H) carboxamide I-241A^(b) (3R)-3-((S)-1-(2-fluoro-3- 121 524.32.24 (s, 3H), 2.32 (m, 2H), 2.75 (s, 3H), methylphenyl)-1-hydroxy-5-3.26 (s, 3H), 3.32 (m, 2H), 3.76 (m, 1H), methoxypentyl)-N-((S)-3-(4-4.22 (m, 2H), 6.05 (m, 1H), 6.97 (m, 1H), fluorocyclohexyl)-1- 7.00 (m,1H), 7.35 (m, 1H), 8.82 (brs, 1H), (methylamino)propan-2- 9.91 (brs, 1H)yl)piperidine-1-carboxamide I-242A (3R)-3-((S)-1-(2-(3- 119 524.3 0.85(m, 6H), 2.34 (m, 3H), 2.55 (m, 1H), methylphenyl)phenyl)-1-hydroxy-5-2.66 (s, 3H), 2.75 (m, 1H), 2.92 (m, 1H),methoxypentyl)-N-((S)-4-methyl-1- 3.28 (s, 3H), 3.91 (m, 3H), 6.96 (m,3H), (methylamino)pentan-2- 7.15 (m, 3H), 7.30 (m, 1H), 7.58 (m, 1H)yl)piperidine-1-carboxamide I-243A (3R)-3-((S)-1-(2-(4- 119 524.4 0.88(m, 6H), 1.75 (m, 1H), 2.37 (s, 3H), methylphenyl)phenyl)-1-hydroxy-5-2.57 (m, 1H), 2.66 (s, 3H), 2.86 (m, 1H),methoxypentyl)-N-((S)-4-methyl-1- 3.03 (m, 1H), 3.27 (m, 3H), 3.98 (m,3H), (methylamino)pentan-2- 6.90 (d, 1H), 6.926-7.22 (m, 5H),yl)piperidine-1-carboxamide 7.32 (t, 1H), 7.70 (d, 1H) I-244A(3R)-3-((S)-1-(3-chlorophenyl)-1- 117 1.51 524 0.98 (m), 1.20-2.04 (m),2.60 (m), hydroxy-5-methoxypentyl)- 2.74 (s), 3.14 (dd), 3.22 (dd), 3.24(s), N-((1R,2R)-1-cyclohexyl-1-hydroxy-3- 3.28 (tm), 3.98 (d), 4.24 (m),7.22-7.34 (m), (methylamino)propan-2- 7.42 (s)yl)piperidine-1-carboxamide I-244B (3R)-3-((S)-1-(3-chlorophenyl)-1- 1171.45 524 0.98-2.02 (m), 2.54 (m), 2.74 (s), hydroxy-5-methoxypentyl)-3.04 (m), 3.26 (s), 3.28 (t), 3.42 (m), 3.84,N-((1S,2R)-1-cyclohexyl-1-hydroxy-3- 3.98 (d), 4.08 (m), 4.28, 4.42 (d),(methylamino)propan-2- 7.22-7.34 (m), 7.42 (s)yl)piperidine-1-carboxamide I-245A (3R)-3-((S)-1-(3-chlorophenyl)-1- 1131.47 524, 7.43 (t, 1H), 7.32-7.21 (m, 3H), 4.42hydroxy-5-methoxypentyl)-N-(3-(1- 526 and 4.29 (two isomers on 1 to 1ratio, hydroxycyclohexyl)-1- d, 1H), 4.15 (m, 1H), 3.95 and 3.83 (two(methylamino)propan-2- isomers on 1 to 1 ratio, d, 1H), 3.34 (m,yl)piperidine-1-carboxamide 1H), 3.27 (s, 3H), 3.14 (m, 1H), 2.99 (m,1H), 2.80 (s, 3H), 2.64-2.38 (m, 3H), 1.94 (t, 2H), 1.76 (m, 2H),1.68-1.18 (m, 20H), 0.98 (m, 1H) I-246A(3R)-3-((S)-1-(3-chlorophenyl)-1- 116 1.41 524, 7.43 (d, 1H), 7.33-7.21(m, 3), 4.37 (t, hydroxy-5-methoxypentyl)-N-(3-(1- 526 1H), 3.88 (t,1H), 3.54 (m, 1H), 3.40 (m, hydroxycyclohexyl)-2- 1H), 3.33 (m, 1H),3.27 (s, 3H), 2.60 (q, (methylamino)propyl)piperidine-1- 1H), 2.46 (m,1H), 1.94 (t, 2H), 1.86 (dt, carboxamide 1H), 1.76 (tt, 1H), 1.68-1.21(m 18H), 0.99 (m, 1H). I-247A (3R)-3-((S)-1-(3-chlorophenyl)-1- 123 1.77525 2.67 (s), 3.20 (s), 5.12 (m), 7.39 (s)hydroxy-5-methoxypentyl)-N-((S)-3- cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carbothioamide I-248A^(b) (3R)-N-((S)-3-cyclohexyl-1-121 525.3 2.18 (s, 3H), 2.40 (m, 1H), 2.73 (m, 2H),(methylamino)propan-2-yl)-3-((S)-1- 3.03 (m, 1H), 3.26 (s, 3H), 3.90 (m,1H), hydroxy-5-methoxy-1-(quinolin-8- 4.26 (m, 1H), 4.62 (m, 1H), 6.34(m, 1H), yl)pentyl)piperidine-1-carboxamide 7.80-8.11 (m, 3H), 8.35 (m,1H), 8.90 (m, 1H), 9.18 (m, 1H), 9.39 (m, 1H) I-249A(R)-3-((S)-1-(2-(p-tolyloxy)-5- 33 1.66 526 0.92 (m), 1.20-1.60 (m),1.30 (s), methylphenyl)-1-hydroxy-5- 1.84 (m), 2.20 (m), 2.28 (s), 2.30(s), methoxypentyl)-N-(2-methyl-1- 2.64 (s), 2.72 (m), 3.10 (dd), 3.24(s), (methylamino)propan-2- 3.26 (t), 3.82 (d), 4.38 (d), 6.62 (d), 6.78(d), yl)piperidine-1-carboxamide 6.98 (dd), 7.12 (d), 7.42 (d)I-250A^(b) (3R)-3-((S)-1-(3-chloro-5- 121 526.3 2.62 (m, 1H), 2.82 (s,3H), 3.28 (s, 3H), fluorophenyl)-1-hydroxy-5- 3.79 (m, 1H), 4.28 (m,2H), 5.95 (m, 1H), methoxypentyl)-N-((S)-3-cyclohexyl- 6.98 (m, 2H),7.12 (m, 1H), 8.91 (brs, 1H), 1-(methylamino)propan-2- 9.76 (brs, 1H)yl)piperidine-1-carboxamide I-251A (3R)-3-(1-(3-chloro-2-fluorophenyl)-33 1.63 526 7.52 (m, 1H), 7.36 (m, 1H), 7.12 (m,1-hydroxy-5-methoxypentyl)-N-((S)- 1H), 4.32 (d, J = 12.9, 1H), 4.12 (m,3-cyclohexyl-1- 1H), 3.99 (d, J = 12.9, 1H), 3.30 (s, 3H),(methylamino)propan-2- 2.70, (s, 3H) yl)piperidine-1-carboxamide I-251B(3R)-3-((S)-1-(3-chloro-2- 33 1.63 526 7.52 (m, 1H), 7.36 (m, 1H), 7.12(m, fluorophenyl)-1-hydroxy-5- 1H), 6.76 (s, 2H), 4.32 (d, J = 12.9,1H), methoxypentyl)-N-((S)-3-cyclohexyl- 4.12 (m, 1H), 3.99 (d, J =12.9, 1H), 1-(methylamino)propan-2- 3.30 (s, 3H), 2.70, (s, 3H)yl)piperidine-1-carboxamide I-252A^(b) (3R)-3-((S)-1-(3-chloro-2- 119526.3 1.16 (t, 3H), 2.32 (m, 1H), 2.73 (s, 3H),fluorophenyl)-5-ethoxy-1- 3.16 (m, 1H), 3.35 (s, 3H), 3.74 (m, 1H),hydroxypentyl)-N-((S)-3- 4.15 (m, 2H), 5.94 (m, 1H), 7.06 (dd, 1H),cyclopentyl-1-(methylamino)propan- 7.28 (dd, 1H), 7.49 (dd, 1H), 8.99(brs, 1H), 2-yl)piperidine-1-carboxamide 9.84 (brs, 1H) I-253A^(b)(3R)-3-((S)-1-(3-chlorophenyl)-1- 119 526.5 2.52 (m, 1H), 2.73 (s, 3H),3.76 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-3- 4.28 (m, 2H), 6.24 (m,1H), 7.22 (m, 3H), (4-fluorocyclohexyl)-1- 7.36 (m, 1H), 9.21 (brs, 1H),9.78 (brs, 1H) (methylamino)propan-2- yl)piperidine-1-carboxamide I-254A(3R)-3-((S)-1-hydroxy-5-methoxy-1- 33 1.22 527 8.47 (d, 2H), 7.85-7.72(m, 3H), 7.33 (m, (2-(pyridin-3-yloxy)phenyl)pentyl)- 2H), 6.93 (dd,1H), 4.05 (m, 1H), 3.03 (d, N-((S)-4-methyl-1- 1H), 2.68 (s, 3H)(methylamino)pentan-2- yl)piperidine-1-carboxamide I-255A^(b)(3R)-3-((R)-(3-ethoxypropoxy)(3- 121 528 1.14 (m, 3H), 2.06 (m, 2H),2.70 (s, 3H), fluorophenyl)methyl)-N-((S)-3-(4,4- 3.79 (m, 1H), 3.93 (d,1H), 4.15 (m, 2H), difluorocyclohexyl)-1- 5.83 (m, 1H), 6.98 (m, 3H),7.32 (m, 1H), (methylamino)propan-2- 8.80 (brs, 1H), 9.82 (brs, 1H)yl)piperidine-1-carboxamide I-256A (3R)-N-((S)-3-cyclohexyl-1- 33 1.56528 7.15 (m, 1H), 7.05 (m, 1H), 6.38 (d, J = 8.6,(methylamino)propan-2-yl)-3-(1- 1H), 4.32 (d, J = 12.5, 1H),(2,3,5-trifluorophenyl)-1-hydroxy-5- 4.12 (m, 1H), 3.99 (d, J = 13.7,1H), 3.29 (s, methoxypentyl)piperidine-1- 3H), 2.70, (s, 3H) carboxamideI-256B (3R)-N-((S)-3-cyclohexyl-1- 33 1.56 528 7.15 (m, 1H), 7.05 (m,1H), 6.70 (s, 2H), (methylamino)propan-2-yl)-3-((S)-1- 4.32 (d, J =12.5, 1H), 4.12 (m, 1H), (2,3,5-trifluorophenyl)-1-hydroxy-5- 3.99 (d, J= 13.7, 1H), 3.29 (s, 3H), methoxypentyl)piperidine-1- 2.70, (s, 3H)carboxamide I-257A^(b) (3R)-N-((S)-3-cyclopentyl-1- 119 530.6 1.15 (t,3H), 2.42 (m, 1H), 2.55 (m, 1H), (methylamino)propan-2-yl)-3-((S)-5-2.64 (t, 1H), 2.73 (m, 1H), 2.80 (s, 3H),ethoxy-1-(2,3,5-trifluorophenyl)-1- 2.96 (m, 1H), 3.28 (m, 2H), 3.36 (t,2H), hydroxypentyl)piperidine-1- 3.44 (m, 2H), 3.75 (m, 1H), 4.23 (m,1H), carboxamide 4.36 (m, 1H), 6.18 (m, 1H), 6.80 (m, 1H), 7.06 (m, 1H),9.01 (brs, 1H), 9.87 (brs, 1H) I-258A (3R)-3-((S)-1-(2-(2- 112 1.47 5280.98 (m), 1.08 (t), 1.24-1.64 (m), ethylphenoxy)phenyl)-1-hydroxy-5-1.94 (m), 2.42 (m), 2.62 (q), 2.64 (s),methoxypentyl)-N-((R)-3-hydroxy-1- 2.82 (m), 3.04 (m), 3.22 (m), 3.24(s), (methylamino)propan-2- 3.26 (t), 6.56 (d), 6.74 (d), 7.04-7.20 (m),yl)piperidine-1-carboxamide 7.32 (d), 7.62 (d) I-259A^(b)(3R)-3-((S)-1-(3-fluoro-2- 119 528.3 0.86 (t, 6H), 2.69 (s, 3H), 3.14(m, 1H), phenylphenyl)-1-hydroxy-5- 3.28 (s, 3H), 3.80 (m, 2H), 4.13 (m,1H), methoxypentyl)-N-((S)-4-methyl-1- 5.70 (m, 1H), 7.00 (t, 1H), 7.28(m, 7H), (methylamino)pentan-2- 8.46 (brs, 1H), 9.54 (brs, 1H)yl)piperidine-1-carboxamide I-260A (3R)-3-((S)-1-(2-(2- 119 528.4 0.91(m, 6H), 2.67 (s, 3H), 3.33 (m, 3H), fluorophenyl)phenyl)-1-hydroxy-5-3.98 (m, 1H), 6.96 (m, 1H), methoxypentyl)-N-((S)-4-methyl-1- 7.13-7.38(m, 6H), 7.38 (m, 1H) (methylamino)pentan-2- yl)piperidine-1-carboxamideI-261A (3R)-3-((S)-1-(2-(3- 119 528.4 0.90 (m, 6H), 1.78 (m, 1H), 2.56(m, 1H), fluorophenyl)phenyl)-1-hydroxy-5- 2.67 (s, 3H), 2.83 (m, 2H),3.04 (m, 1H), methoxypentyl)-N-((S)-4-methyl-1- 3.30 (s, 3H), 3.98 (m,3H), (methylamino)pentan-2- 6.83-6.95 (m, 4H), 7.32 (m, 1H), 7.37 (m,2H), yl)piperidine-1-carboxamide 7.71 (m, 1H) I-262A(3R)-3-((S)-1-(2-(4- 119 528.4 0.89 (m, 6H), 1.74 (m, 1H), 2.56 (m, 1H),fluorophenyl)phenyl)-1-hydroxy-5- 2.68 (s, 3H), 2.87 (m, 2H), 3.05 (m,1H), methoxypentyl)-N-((S)-4-methyl-1- 3.30 (m, 3H), 3.99 (m, 3H), 6.93(m, 1H), (methylamino)pentan-2- 7.07-7.24 (m, 5H), 7.35 (t, 1H),yl)piperidine-1-carboxamide 7.72 (m, 1H) I-263A(3R)-3-(1-(3-chlorophenyl)-5,5- 33 1.71 528 7.33 (s), 7.22-7.11 (m),4.18 (d), difluoro-1-hydroxyhexyl)-N-((S)-3- 4.00 (m), 3.84 (d), 3.18(m), 2.94 (d), cyclohexyl-1-(methylamino)propan- 2.80 (t), 2.58 (s),2.46-2.34 (m), 1.35 (t). 2-yl)piperidine-1-carboxamide I-264A^(b)(3R)-3-((R)-(3- 121 528.3 1.15 (t, 3H), 3.28 (s, 3H), 3.82 (m, 1H),methoxypropoxy)(2,3- 4.02 (m, 1H), 4.17 (m, 1H), 4.57 (m, 1H),dichlorophenyl)methyl)-N-((S)-3- 5.61 (m, 1H), 7.22 (m, 1H), 7.31 (m,1H), cyclohexyl-1-(methylamino)propan- 7.39 (m, 1H), 8.79 (brs, 1H),9.85 (brs, 1H) 2-yl)piperidine-1-carboxamide I-265A^(b)(3R)-3-((S)-1-(2,3-dichlorophenyl)- 119 528.3 3.28 (s, 3H), 3.83 (m,1H), 3.95 (m, 1H), 1-hydroxy-5-methoxypentyl)-N-((S)- 2.78 (s, 3H), 3.42(t, 3H), 5.85 (m, 1H), 3-cyclopentyl-1- 7.10 (m, 1H), 7.21 (s, 1H), 7.28(m, 2H), (methylamino)propan-2- 8.65 (brs, 1H), 9.71 (brs, 1H)yl)piperidine-1-carboxamide I-266A^(b)(3R)-3-((R)-(3-ethoxypropoxy)(2,3- 119 528.5 1.15 (t, 3H), 2.68 (s, 3H),2.96 (m, 1H), dichlorophenyl)methyl)-N-((S)-3- 3.09 (m, 1H), 3.28 (t,3H), 3.45 (m, 2H), cyclopentyl-1-(methylamino)propan- 3.83 (m, 1H), 4.58(d, 2H), 5.60 (m, 1H), 2-yl)piperidine-1-carboxamide 7.24 (m, 1H), 7.30(m, 1H), 7.40 (d, 1H), 8.69 (brs, 1H), 9.87 (brs, 1H) I-267A(3R)-3-((S)-1-(benzo[b]thiophen-7- 33 1.67 530 7.72 (dd, 1H), 7.48 (t,1H), 7.35-7.24 (m, yl)-1-hydroxy-5-methoxypentyl)- 3H), 4.12 (m, 1H),3.05 (dt, 1H), 2.71 (s, N-((S)-3-cyclohexyl-1- 3H), 1.83 (d, 1H), 1.03(m, 1H), 0.91 (m, (methylamino)propan-2- 1H).yl)piperidine-1-carboxamide I-268A (3R)-3-((S)-1-(benzo[b]thiophen-2- 331.63 530 7.78 (d, 1H), 7.71 (d, 1H), 7.33-7.23 (m,yl)-1-hydroxy-5-methoxypentyl)- 2H), 7.16 (d, 1H), 4.29 (d, 1H), 4.12(m, N-((S)-3-cyclohexyl-1- 1H), 4.01 (d, 2H). (methylamino)propan-2-yl)piperidine-1-carboxamide I-269A (3R)-3-((S)-1-hydroxy-5-methoxy-1- 331.62 532 0.98 (s), 1.08-1.78 (m), 1.94 (m),(3-(trifluoromethoxy)phenyl)pentyl)- 2.46 (m), 2.68 (s), 2.94 (dd), 3.02(dd), N-((S)-4,4-dimethyl-1- 3.24 (s), 3.26 (t), 3.98 (d), 4.18 (m),4.32 (d), (methylamino)pentan-2- 7.14 (d), 7.34 (m), 7.42 (m)yl)piperidine-1-carboxamide I-270A (3R)-N-((S)-3-cyclohexyl-1- 33 1.55532 7.73 (s, 0.5H), 7.39 (m, 0.5H), (methylamino)propan-2-yl)-3-((S)-1-7.32-7.19 (m, 1.5H), 6.98 (t, 0.5H), 6.85 (m,(5-fluorobenzofuran-7-yl)-1- 0.5H), 6.73 (s, 0.5H), 2.43 (td, 1H),hydroxy-5- 2.26 (t, 1H). methoxypentyl)piperidine-1- carboxamide I-271A(3R)-3-((S)-1-(3-chlorophenyl)-1- 125 1.62 532 2.98 (m), 3.25 (s), 4.09(m), 4.33 (m), hydroxy-5-methoxypentyl)-N′- 7.11-7.18 (m), 7.46 (s)cyano-N-((S)-3-cyclohexyl-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-272A (3R)-3-((S)-1-acetamido-1-(3- 133 1.4533 7.84 (s, 1H), 7.30-7.24 (m, 1H), fluorophenyl)-5-methoxypentyl)-7.06-6.89 (m, 3H), 4.10 (d, J = 12.6 Hz, 1H), N-((S)-3-cyclohexyl-1-4.05-3.98 (m, 1H), 3.79 (d, J = 12.9 Hz, (methylamino)propan-2- 1H),3.30 (t, J = 6.3 Hz, 2H), yl)piperidine-1-carboxamide 3.00-2.86 (m, 2H),2.63 (s, 3H), 1.99 (s, 3H). I-273A (3R)-3-((S)-1-(3-chloro-2- 33 1.45534 7.42 (t), 7.26 (t), 7.03 (t), 4.30 (m), fluorophenyl)-1-hydroxy-5-3.91 (m), 3.78 (m), 3.20 (s), 3.14 (s), methoxypentyl)-N-(3-(3,3- 3.08(m), 2.88 (t) 2.60 (s). difluorocyclobutyl)-1- (methylamino)propan-2-yl)piperidine-1-carboxamide I-274A N-((S)-3-cyclohexyl-1- 129 1.65 535not determined (methylamino)propan-2-yl)-3-(1-(3-(trifluoromethyl)phenyl)-1-hydroxy- 5-methoxypentyl)benzamide I-275A(3R)-3-((S)-1-(2-(o-tolyloxy)phenyl)- 33 1.59 540 0.64, 0.78 (d), 0.96(m), 1.14-1.66 (m), 1-hydroxy-5-methoxypentyl)-N-((S)- 1.98 (m), 2.20(s), 2.42 (m), 2.62 (m), 4-methyl-1-(methylamino)pentan-2- 2.64 (s),2.86 (m), 3.00 (m), 3.24 (s), yl)piperidine-1-carboxamide 3.26 (t), 4.04(m), 4.26 (d), 6.42 (d), 6.78 (d), 7.02 (m), 7.08 (m), 7.18 (d), 7.28(d), 7.62 (d) I-276A (3R)-3-((S)-1-hydroxy-5-methoxy-1- 33 1.64 540 0.86(s), 1.20-1.64 (m), 1.94 (m), (2-phenoxyphenyl)pentyl)-N-((S)- 2.24 (m),2.32 (m), 2.58 (m), 2.64 (s), 4,4-dimethyl-1- 2.88 (m), 2.98 (dd), 3.24(s), 3.26 (t), (methylamino)pentan-2- 4.02 (d), 4.12 (m), 4.24 (d), 6.76(d), yl)piperidine-1-carboxamide 6.92 (d), 7.12 (m), 7.18 (m), 7.36 (m),7.64 (d) I-277A (3R)-3-(1-(2-(benzyloxy)phenyl)-1- 33 1.61 540 7.49-6.82(m), 5.01 (m), 4.13 (br m), hydroxy-5-methoxypentyl)-N-((S)-4- 3.88 (m),3.77 (m), 3.20 (s), 3.13 (d), methyl-1-(methylamino)pentan-2- 2.57 (s),2.51 (s), 0.83-0.70 (m) yl)piperidine-1-carboxamide I-278A(3R)-3-((S)-1-(2-(m- 33 1.63 540 0.88 (d), 0.94 (d), 0.96 (m),tolyloxy)phenyl)-1-hydroxy-5- 1.20-1.70 (m), 1.94 (m), 2.26 (s), 2.60(m), methoxypentyl)-N-((S)-4-methyl-1- 2.66 (s), 2.88 (m), 3.04 (dd),3.24 (s), (methylamino)pentan-2- 3.26 (t), 4.00 (m), 4.26 (d), 6.72 (m),yl)piperidine-1-carboxamide 6.96 (d), 7.06 (m), 7.18 (m), 7.22 (m), 7.62(d) I-279A^(b) (3R)-3-(1-(3-chloro-2-fluorophenyl)- 33 1.65 541 7.53 (t,J = 6.6, 1H), 7.37 (t, J = 7.02, 5-ethoxy-1-hydroxypentyl)-N-((S)-3-1H), 7.14 (t, J = 7.8, 1H), 4.33 (d, J = 14,cyclohexyl-1-(methylamino)propan- 1H), 4.13 (m, 1H), 3.99 (d, J = 12.52-yl)piperidine-1-carboxamide 1H), 33.40 (q, J = 7.0, 2H), 2.70 (s, 3H)I-279A (3R)-3-((S)-1-(3-chloro-2- 121 540.3 1.19 (t, 3H), 1.86 (m, 2H),2.33 (m, 1H), fluorophenyl)-5-ethoxy-1- 2.68 (m, 2H), 2.77 (s, 3H), 2.92(m, 1H), hydroxypentyl)-N-((S)-3-cyclohexyl- 3.22 (m, 1H), 3.37 (t, 2H),3.42 (t, 2H), 1-(methylamino)propan-2- 3.74 (m, 1H), 4.14 (m, 1H), 4.26(m, 1H), yl)piperidine-1-carboxamide 5.98 (m, 1H), 7.06 (dd, 1H), 7.30(dd, 1H), 7.50 (dd, 1H), 8.81 (brs, 1H), 9.76 (brs, 1H) I-280A(3R)-3-((S)-1-(3-chloro-2- 121 1.68 540 7.43 (t), 7.28 (t), 7.04 (t),3.21 (m), fluorophenyl)-1-hydroxy-5- 3.16 (s), 2.62 (s), 0.84 (m).methoxypentyl)-N-(1- (methylamino)-3-(4- methylcyclohexyl)propan-2-yl)piperidine-1-carboxamide I-281A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121542.3 0.92 (m, 3H), 2.75 (s, 3H), 3.27 (s, 3H),(methylamino)propan-2-yl)-3-((S)-1- 3.77 (m, 1H), 4.24 (m, 2H), 5.75 (m,1H), (2-(trifluoromethyl)phenyl)-1- 7.32 (t, 1H), 7.76 (d, 1 H), 8.08(m, 1H), hydroxy-5- 8.38 (brs, 1H), 9.64 (brs, 1H)methoxypentyl)piperidine-1- carboxamide I-282A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 542.6 1.15 (t, 3H), 2.34 (t, 1H), 2.68(m, 2H), (methylamino)propan-2-yl)-3-((S)-5- 2.79 (s, 3H), 2.92 (m, 1H),3.24 (m, 1H), ethoxy-1-(2,3,5-trifluorophenyl)-1- 3.39 (t, 2H), 3.49 (m,2H), 3.79 (m, 1H), hydroxypentyl)piperidine-1- 4.26 (m, 2H), 6.02 (m,1H), 6.80 (m, 1H), carboxamide 7.06 (m, 1H), 8.68 (brs, 1H), 9.76 (brs,1H) I-283A (3R)-3-((S)-1-(2-fluoro-3- 121 542.4 0.85 (m, 1H), 2.25 (m,3H), 2.54 (m, 1H), methylphenyl)-1-hydroxy-5- 2.72 (s, 3H), 2.88 (m,2H), 3.10 (m, 1H), methoxypentyl)-N-((S)-3-(4,4- 3.26 (s, 3H), 3.30 (t,2H), 4.02 (m, 1H), difluorocyclohexyl)-1- 4.14 (m, 1H), 4.30 (m, 1H),7.02 (m, 1H), (methylamino)propan-2- 7.11 (t, 1H), 7.36 (t, 1H)yl)piperidine-1-carboxamide I-284A^(b)(3R)-3-((S)-1-(2,3-dichlorophenyl)- 121 542.3 1.88 (m, 1H), 2.52 (m,1H), 2.75 (s, 3H), 1-hydroxy-5-methoxypentyl)-N-((S)- 2.96 (m, 1H), 3.28(s, 3H), 3.34 (m, 2H), 3-cyclohexyl-1- 3.79 (m, 1H), 3.97 (m, 1H), 4.24(m, 1H), (methylamino)propan-2- 5.80 (m, 1H), 7.19 (m, 1H), 7.38 (m,1H), yl)piperidine-1-carboxamide 7.72 (m, 1H), 8.59 (brs, 1H), 9.70(brs, 1H) I-285A^(b) (3R)-3-((R)-(3-ethoxypropoxy)(2,3- 121 542.3 1.19(t, 3H), 2.90 (m, 1H), 3.06 (m, 1H), dichlorophenyl)methyl)-N-((S)-3-3.30 (t, 3H), 3.82 (m, 1H), 4.02 (m, 1H),cyclohexyl-1-(methylamino)propan- 4.13 (m, 1H), 4.57 (m, 1H), 4.91 (m,1H), 2-yl)piperidine-1-carboxamide 5.59 (m, 1H), 7.22 (m, 1H), 7.30 (m,1H), 7.41 (m, 1H), 8.76 (brs, 1H), 9.81 (brs, 1H) I-286A^(b)(3R)-3-((S)-1-(2,3-dichlorophenyl)- 119 542.4 1.15 (t, 3H), 2.52 (m,1H), 2.73 (s, 3H), 5-ethoxy-1-hydroxypentyl)-N-((S)-3- 3.05 (m, 2H),3.24 (m, 1H), 3.35 (m, 2H), cyclopentyl-1-(methylamino)propan- 3.45 (m,2H), 4.06 (m, 1H), 4.18 (m, 1H), 2-yl)piperidine-1-carboxamide 5.87 (m,1H), 7.19 (m, 1H), 7.38 (d, 1H), 7.75 (d, 1H), 8.68 (brs, 1H), 9.80(brs, 1H) I-287A (3R)-3-((S)-1-(2-(4- 33 1.56 544 0.78, 0.84 (d), 0.94(m), 1.20-1.68 (m), fluorophenoxy)phenyl)-1-hydroxy-5- 1.96 (m), 2.24(m), 2.62 (m), 2.64 (s), methoxypentyl)-N-((S)-4-methyl-1- 2.88 (m),3.04 (dd), 3.24 (s), 3.26 (t), (methylamino)pentan-2- 4.00 (m), 4.26(d), 6.64 (d), 6.94 (m), yl)piperidine-1-carboxamide 7.06-7.20 (m), 7.64(dd) I-288A (3R)-3-((S)-1-(5-fluoro-2- 33 1.60 544 0.78, 0.84 (d), 0.94(m), 1.20-1.68 (m), phenoxyphenyl)-1-hydroxy-5- 1.96 (m), 2.24 (m), 2.62(m), 2.64 (s), methoxypentyl)-N-((S)-4-methyl-1- 2.84 (m), 3.04 (dd),3.24 (s), 3.26 (t), (methylamino)pentan-2- 3.98 (d), 4.00 (m), 4.26 (d),6.74 (dd), yl)piperidine-1-carboxamide 6.92 (m), 7.12 (m), 7.38 (m),7.40 (dd) I-289A (3R)-3-((S)-1-(2-(3- 33 1.55 544 0.82, 0.86 (d),1.20-1.70 (m), 1.96 (m), fluorophenoxy)phenyl)-1-hydroxy-5- 2.18 (m),2.60 (m), 2.66 (s), 2.86 (m), methoxypentyl)-N-((S)-4-methyl-1- 3.04(m), 3.24 (s), 3.26 (t), 3.98 (d), (methylamino)pentan-2- 4.02 (m), 4.26(d), 6.64 (dd), 6.76 (dd), yl)piperidine-1-carboxamide 6.84 (m), 7.16(m), 7.24 (m), 7.38 (m), 7.64 (dd) I-290A (3R)-3-((S)-1-(2-(2- 33 1.53544 7.63 (dd, 1H), 7.28-7.13 (m, 4H), 7.08 (m,fluorophenoxy)phenyl)-1-hydroxy-5- 2H), 6.57 (d, 1H), 4.28 (d, 1H), 4.00(m, methoxypentyl)-N-((S)-4-methyl-1- 2H), 3.24 (s, 3H), 3.02 (dd, 1H),2.66 (s, (methylamino)pentan-2- 3H), 1.96 (td, 1H), 0.93 (m, 1H),yl)piperidine-1-carboxamide 0.83-0.71 (dd, 6H). I-290B(3R)-3-((R)-1-(2-(2- 33 1.6 544 7.65 (dd, 1H), 7.26-7.13 (m, 4H),fluorophenoxy)phenyl)-1-hydroxy-5- 7.09-6.99 (m, 2H), 6.59 (d, 1H), 4.48(d, 1H), methoxypentyl)-N-((S)-4-methyl-1- 4.06 (m, 1H), 3.24ls, 3H),3.03 (dd, 1H), (methylamino)pentan-2- 2.89 (t, 1H), 2.67 (s, 3H), 1.94(td, 1H), yl)piperidine-1-carboxamide 0.92-0.81 (dd, 6H), I-291A(3R)-3-((S)-1-(3-fluoro-2- 33 1.56 544 0.82 (m), 0.88, 0.92 (d),1.08-1.70 (m), phenoxyphenyl)-1-hydroxy-5- 1.92 (m), 2.04 (m), 2.58 (m),2.64 (s), methoxypentyl)-N-((S)-4-methyl-1- 2.84 (m), 3.04 (m), 3.20(t), 3.22 (s), (methylamino)pentan-2- 3.94 (d), 4.02 (m), 4.24 (d), 6.80(d), yl)piperidine-1-carboxamide 7.02 (m), 7.14 (m), 7.22 (m), 7.26 (m),7.52 (d) I-292A (3R)-3-((S)-1-(3-(4- 33 1.57 544 0.92 (d), 0.96 (d),1.04 (m), fluorophenoxy)phenyl)-1-hydroxy-5- 1.20-1.78 (m), 1.84 (m),1.92 (m), 2.56 (m), methoxypentyl)-N-((S)-4-methyl-1- 2.68 (s), 2.92(dd), 3.06 (dd), 3.24 (s), (methylamino)pentan-2- 3.26 (t), 3.96 (d),4.06 (m), 4.28 (d), 6.82 (d), yl)piperidine-1-carboxamide 6.96-7.14 (m),7.32 (m) I-293A^(b) (3R)-3-((S)-1-(3-chlorophenyl)-1- 33 544.3 2.25 (dd,1H), 2.56 (dd, 1H), 2.80 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-3-3.28 (s, 3H), 3.31 (t, 3H), 3.73 (m, 1H), (4,4-difluorocyclohexyl)-1-3.74 (m, 1H), 6.14 (m, 1H), (methylamino)propan-2- 7.16-7.24 (m, 2H),7.35 (s, 1H), 8.84 (brs, 1H), yl)piperidine-1-carboxamide 9.62 (brs, 1H)I-294A^(b) (3R)-3-((R)-(3-ethoxypropoxy)(3- 33 544.3 1.13 (t, 3H), 2.78(s, 3H), 3.42 (t, 3H), chlorophenyl)methyl)-N-((S)-3-(4,4- 5.85 (m, 1H),7.10 (m, 1H), 7.21 (s, 1H), difluorocyclohexyl)-1- 7.28 (m, 2H), 8.65(brs, 1H), 9.71 (brs, 1H) (methylamino)propan-2-yl)piperidine-1-carboxamide I-295A^(b) (3R)-3-((S)-1-(3-chloro-2- 119544.5 2.77 (s, 3H), 2.92 (m, 2H), 3.29 (s, 3H),fluorophenyl)-1-hydroxy-5- 3.33 (m, 2H), 3.89 (m, 1H), 4.12 (m, 1H),methoxypentyl)-N-((S)-3-(trans-4- 4.39&4.52 (m, 1H), 6.08 (m, 1H),fluorocyclohexyl)-1- 7.06 (t, 1H), 7.29 (t, 1H), 7.51 (t, 1H),(methylamino)propan-2- 8.88 (brs, 1H), 9.47 (brs, 1H)yl)piperidine-1-carboxamide I-295B^(b) (3R)-3-((S)-1-(3-chloro-2- 119544.5 0.92 (m, 2H), 2.75 (s, 3H), 3.29 (s, 3H),fluorophenyl)-1-hydroxy-5- 3.93 (m, 1H), 4.12 (m, 1H), 4.32 (m, 1H),methoxypentyl)-N-((S)-3-(4- 6.15 (m, 1H), 7.06 (t, 1H), 7.28 (m, 1H),fluorocyclohexyl)-1- 7.51 (t, 1H), 8.84 (brs, 1H), 9.28 (brs, 1H)(methylamino)propan-2- yl)piperidine-1-carboxamide I-296A(3R)-3-((S)-1-(2-(2- 119 544.4 0.88 (m, 6H), 2.59 (m, 1H), 2.68 (m, 3H),chlorophenyl)phenyl)-1-hydroxy-5- 2.72 (m, 2H), 3.05 (m, 1H), 3.25 (m,3H), methoxypentyl)-N-((S)-4-methyl-1- 3.46 (m, 2H), 4.00 (m, 3H), 6.94(m, 3H), (methylamino)pentan-2- 7.16-7.48 (m, 6H), 7.58 (m, 1H)yl)piperidine-1-carboxamide I-296A^(b) (3R)-3-((S)-1-(2-(2- 119 544.20.94 (m, 6H), 2.72 (m, 3H), 2.98 (m, 3H),chlorophenyl)phenyl)-1-hydroxy-5- 3.28 (s, 3H), 3.33 (m, 2H), 3.72 (m,1H), methoxypentyl)-N-((S)-4-methyl-1- 4.15 (m, 2H), 5.72 (m, 1H), 6.98(m, 2H), (methylamino)pentan-2- 7.20 (m, 2H), 7.48 (m, 4H), 8.75 (brs,1H), yl)piperidine-1-carboxamide 10.08 (brs, 1H) I-296B^(b)(3R)-3-((R)-1-(2-(2- 119 544.2 0.88 (m, 6H), 2.73 (s, 3H), 3.29 (s, 3H),chlorophenyl)phenyl)-1-hydroxy-5- 3.33 (m, 2H), 3.80 (m, 1H), 4.28 (m,2H), methoxypentyl)-N-((S)-4-methyl-1- 5.42 (m, 1H), 7.00 (m, 2H), 7.19(m, 2H), (methylamino)pentan-2- 7.38 (m, 1H), 7.52 (m, 3H), 8.70 (brs,1H), yl)piperidine-1-carboxamide 10.02 (brs, 1H) I-297A(3R)-3-((S)-1-(2-(4- 119 544.3 0.90 (m, 6H), 1.78 (m, 1H), 2.57 (m, 1H),chlorophenyl)phenyl)-1-hydroxy-5- 2.68 (s, 3H), 2.82 (m, 2H), 3.03 (m,1H), methoxypentyl)-N-((S)-4-methyl-1- 3.25 (m, 3H), 3.98 (m, 3H), 6.94(m, 1H), (methylamino)pentan-2- 7.05-7.42 (m, 6H), 7.72 (m, 1H)yl)piperidine-1-carboxamide I-298A (3R)-3-((S)-1-(2-(3- 119 544.3 0.92(m, 6H), 1.76 (m, 1H), 2.67 (s, 3H), chlorophenyl)phenyl)-1-hydroxy-5-2.82 (m, 1H), 3.02 (m, 1H), 3.28 (s, 3H),methoxypentyl)-N-((S)-4-methyl-1- 3.99 (m, 1H), 6.95 (m, 1H),(methylamino)pentan-2- 7.05-7.39 (m, 6H), 7.71 (m, 1H)yl)piperidine-1-carboxamide I-299A (3R)-N-((S)-3-(4,4- 33 1.43 546 7.25(m), 7.02 (m), 4.24 (d), 4.02 (m), difluorocyclohexyl)-1- 3.86 (d), 3.19(s), 3.14 (s), 2.99 (d), (methylamino)propan-2-yl)-3-((S)-1- 2.83 (t),2.67 (t), 2.60 (s), 2.54 (t). (2,3-difluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-300A(2RS)-2-((RS)-1-(3-chlorophenyl)-1- 33 1.43 546 7.53 (d, 1H), 7.42 (t,1H), 7.28 (t, 1H), hydroxy-5-methoxypentyl)-N-((S)-3- 7.22 (d, 1H), 4.11(m, 2H), 3.07 (d, 1H), (4,4-difluorocyclohexyl)-1- 2.68 (s, 3H), 1.05(m, 1H). (methylamino)propan-2- yl)morpholine-4-carboxamide I-301A(3R)-3-((S)-1-acetamido-1-(3- 133 1.53 549, 7.86 (s, 1H), 7.27-7.15 (m,4H), 4.10 (d, chlorophenyl)-5-methoxypentyl)- 551 J = 11.4 Hz, 1H),4.03-3.98 (m, 1H), N-((S)-3-cyclohexyl-1- 3.79 (d, J = 13.5 Hz, 1H),3.30 (t, J = 6.1 Hz, (methylamino)propan-2- 2H), 3.00-2.85 (m, 2H), 2.62(s, yl)piperidine-1-carboxamide 3H), 1.98 (s, 3H). I-302A(3R)-3-((S)-1-(benzofuran-7-yl)-1- 121 550.3 0.72 (m, 1H), 2.72 (s, 3H),2.79 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-3- 2.96 (m, 1H), 3.10 (m,1H), 3.18 (s, 3H), (4,4-difluorocyclohexyl)-1- 3.22 (m, 2H), 3.30 (t,2H), 3.98 (m, 1H), (methylamino)propan-2- 4.13 (m, 1H), 4.40 (m, 1H),6.84 (t, 1H), yl)piperidine-1-carboxamide 7.22 (m, 1H), 7.42 (m, 1H),7.52 (m, 1H), 7.68 (m, 1H) I-303A^(b) (3R)-N-((S)-4,4,4-trifluoro-1- 331.49 552 2.40 (d, 3H), 3.25 (s, 3H), 3.79 (m, 1H),(methylamino)butan-2-yl)-3-((S)-1- 6.75 (d, 1H), 6.90 (d, 2H), 7.10 (m,3H), hydroxy-5-methoxy-1-(2- 7.38 (m, 2H), 7.58 (d, 1H)phenoxyphenyl)pentyl)piperidine-1- carboxamide I-304A(3R)-3-((S)-1-(2-(2- 33 1.5 552 7.71 (dd, 2H), 7.56 (t, 1H), 7.28-7.21(m, (trifluoromethyl)phenoxy)phenyl)-1- 2H), 7.16 (t, 1H), 7.00-6.83 (brd, 1H), hydroxy-5-methoxypentyl)-N-((S)-1- 6.71 (d, 1H), 4.31 (d, 1H),2.81 (t, 1H), (methylamino)propan-2- 2.48 (br s, 1H), 0.89 (m, 2H).yl)piperidine-1-carboxamide I-305A^(b) (3R)-N-((S)-1-(2- 33 1.72 5523.25 (s, 3H), 3.75 (m, 1H), methoxyethylamino)-3- 7.10-7.60 (m, 4 H)cyclohexylpropan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-306A(3R)-N-((S)-3-cyclohexyl-1- 33 1.61 554 2.60 (m), 2.71 (s), 2.92 (dd),3.06 (dd), (methylamino)propan-2-yl)-3-((S)-1- 3.13 (s), 4.02 (br d),4.12 (m), 4.35 (br (2,2-difluorobenzo[d][1,3]dioxol-4- d), 7.03-7.09(m), 7.30 (dd) yl)-1-hydroxy-5- methoxypentyl)piperidine-1- carboxamideI-307A (3R)-3-((S)-1-(2-(o-tolyloxy)-3- 33 1.64 554 0.76-1.04 (m),1.20-1.68 (m), 1.92, methylphenyl)-1-hydroxy-5- 1.94 (two s), 2.38, 2.40(two s), 2.50 (m), methoxypentyl)-N-((S)-4-methyl-1- 2.64, 2.70 (two s),2.80-3.16 (m), 3.20, (methylamino)pentan-2- 3.24 (two s), 3.80 (d),3.92-4.22 (m), yl)piperidine-1-carboxamide 6.24 (d), 6.86 (m), 6.98 (m),7.12-7.24 (m), 7.56 (d) I-308A^(b) (3R)-3-((S)-1-(2,3-dichlorophenyl)-121 556.3 1.16 (t, 3H), 1.94 (m, 1H), 2.52 (m, 1H),5-ethoxy-1-hydroxypentyl)-N-((S)-3- 2.74 (s, 3H), 2.96 (m, 1H), 3.13 (m,2H), cyclohexyl-1-(methylamino)propan- 3.36 (t, 3H), 3.45 (m, 2H), 4.22(m, 1H), 2-yl)piperidine-1-carboxamide 5.83 (m, 1H), 7.19 (dd, 1H), 7.38(d, 1H), 7.75 (d, 1H), 8.77 (brs, 1H), 9.78 (brs, 1H) I-309A^(b)(3R)-N-((S)-3-cyclohexyl-1- 121 558.4 1.54 (t, 1H), 2.08 (m, 1H), 2.20(m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 2.55 (t, 1H), 2.82 (s, 3H),2.88 (m, 1H), hydroxy-5-methoxy-1-(3- 3.27 (s, 3H), 3.75 (m, 1H), 3.24(m, 1H), (trifluoromethoxy)phenyl)pentyl)piperidine- 4.24 (m, 2H), 6.03(m, 1H), 7.10 (d, 1H), 1-carboxamide 7.23 (m, 2H), 7.34 (t, 1H), 8.95(brs, 1H), 9.73 (brs, 1H) I-310A^(b) (3R)-N-((S)-3-cyclohexyl-1- 121558.3 2.311.88 (m, 1H), 2.02 (m, 1H),(methylamino)propan-2-yl)-3-((S)-1- 2.25 (m, 1H), 2.74 (s, 3H), 2.95 (m,2H), hydroxy-5-methoxy-1-(2- 3.28 (s, 3H), 3.78 (m, 1H), 4.04 (m, 1H),(trifluoromethoxy)phenyl)pentyl)piperidine- 5.92 (m, 1H), 7.24 (m, 3H),7.69 (d, 1H), 1-carboxamide 8.80 (brs, 1H), 9.62 (brs, 1H) I-311A(3R)-3-((S)-1-(2-(p-tolyloxy)-3- 33 1.63 558 0.82 (m), 0.88, 0.92 (d),1.08-1.68 (m), fluorophenyl)-1-hydroxy-5- 1.92 (m), 2.04 (m), 2.24 (s),2.58 (m), methoxypentyl)-N-((S)-4-methyl-1- 2.64 (s), 2.84 (m), 3.04(m), 3.24 (s), (methylamino)pentan-2- 3.26 (t), 3.94 (d), 4.02 (m), 4.24(d), yl)piperidine-1-carboxamide 6.66 (d), 7.08 (m), 7.20 (m), 7.46 (d)I-312A (3R)-3-((S)-1-(2-(o-tolyloxy)-3- 33 1.59 558 0.70-1.10 (m),1.20-1.78 (m), 1.92 (m), fluorophenyl)-1-hydroxy-5- 2.36, 2.38 (two s),2.50 (m), 2.62, methoxypentyl)-N-((S)-4-methyl-1- 2.72 (two s),2.80-3.08 (m), 3.10, 3.36 (two (methylamino)pentan-2- t), 3.20, 3.26(two s), 3.82 (d), yl)piperidine-1-carboxamide 3.96-4.08 (m), 4.22 (d),6.42, 6.44 (two d), 6.92 (m), 7.02 (m), 7.14 (m), 7.22 (m), 7.54 (d)I-313A (3R)-3-((S)-1-(2-(5-fluoro-2- 33 1.62 558 0.72 (d), 0.80 (d),0.92 (m), methylphenoxy)phenyl)-1-hydroxy- 1.20-1.68 (m), 1.98 (m), 2.20(s), 2.32 (m), 5-methoxypentyl)-N-((S)-4-methyl- 2.60 (m), 2.64 (s),2.84-3.04 (m), 3.24 (s), 1-(methylamino)pentan-2- 3.26 (t), 4.02 (m),4.24 (d), 6.48 (d), yl)piperidine-1-carboxamide 6.58 (d), 6.84 (m), 7.08(m), 7.18 (m), 7.28 (m), 7.64 (d) I-314A (3R)-3-((S)-1-(2-(4-fluoro-2-33 1.61 558 0.70 (d), 0.80 (d), 0.92 (m),methylphenoxy)phenyl)-1-hydroxy- 1.18-1.68 (m), 1.98 (m), 2.20 (s), 2.40(m), 5-methoxypentyl)-N-((S)-4-methyl- 2.62 (m), 2.64 (s), 2.84-3.04(m), 3.24 (s), 1-(methylamino)pentan-2- 3.26 (t), 4.02 (m), 4.26 (d),6.40 (d), yl)piperidine-1-carboxamide 6.78 (m), 6.94 (m), 7.00-7.14 (m),7.62 (d) I-315A (3R)-N-((S)-3-cyclohexyl-1- 33 1.76 558 7.40 (d), 7.34(d), 7.06 (s), 6.76 (s), (methylamino)propan-2-yl)-3-(1-(2- 4.10 (d),3.96 (m), 3.89-3.80 (m), (cyclopentyloxy)phenyl)-1-hydroxy- 3.18 (m),3.14 (m), 3.12 (m), 2.95 (m), 5-methoxypentyl)piperidine-1- 2.84 (q),2.72 (m), 2.58 (s), 2.51 (s). carboxamide I-316A (3R)-3-(1-(2-(2- 331.79 558 7.47 (d), 7.37 (d), 7.13 (q), cyclopropylethoxy)phenyl)-1-6.89-6.05 (m), 4.14 (d), 3.97 (m), 3.88 (m),hydroxy-5-methoxypentyl)-N-((S)-3- 3.21 (m), 3.17 (m), 3.14 (m), 2.61(s), cyclohexyl-1-(methylamino)propan- 2.54 (s), 0.77 (br s), 0.42 (d),0.06 (s). 2-yl)piperidine-1-carboxamide I-317A(3R)-3-((S)-5-ethoxy-1-(2,3- 121 560.3 0.89 (m, 1H), 1.12 (t, 3H), 2.72(s, 3H), difluorophenyl)-1-hydroxypentyl)- 2.95 (m, 1H), 3.09 (m, 1H),3.32 (t, 2H), N-((S)-3-(4,4-difluorocyclohexyl)-1- 3.38 (m, 2H), 3.96(m, 1H), 4.15 (m, 1H), (methylamino)propan-2- 4.36 (m, 1H), 7.13 (m,1H), 7.36 (m, 1H) yl)piperidine-1-carboxamide I-318A(3R)-3-((S)-1-(2-(4-fluorophenoxy)- 33 1.59 562 0.78, 0.86 (d), 0.94(m), 1.20-1.68 (m), 5-fluorophenyl)-1-hydroxy-5- 1.96 (m), 2.24 (m),2.62 (m), 2.64 (s), methoxypentyl)-N-((S)-4-methyl-1- 2.86 (m), 3.04(m), 3.24 (s), 3.26 (t), (methylamino)pentan-2- 3.98 (d), 4.02 (m), 4.28(d), 6.84 (dd), yl)piperidine-1-carboxamide 6.94 (m), 7.10 (m), 7.40(dd) I-318A (3R)-3-((R)-1-(2-(4-fluorophenoxy)- 33 1.65 562 0.94, 0.98(d), 1.24-1.64 (m), 1.78 (m), 5-fluorophenyl)-1-hydroxy-5- 1.96 (m),2.14 (m), 2.64 (m), 2.70 (s), methoxypentyl)-N-((S)-4-methyl-1- 2.78(m), 2.92 (m), 3.08 (m), 3.24 (s), (methylamino)pentan-2- 3.26 (t), 3.98(d), 4.08 (m), 4.34 (d), yl)piperidine-1-carboxamide 6.84 (m), 6.96-7.12(m), 7.24 (m) I-319A (3R)-3-((S)-1-(3,5-difluoro-2- 33 1.60 562 0.88,0.90 (d), 1.10-1.70 (m), 1.96 (m), phenoxyphenyl)-1-hydroxy-5- 2.04 (m),2.58 (m), 2.64 (s), 2.80 (m), methoxypentyl)-N-((S)-4-methyl-1- 3.04(m), 3.24 (st), 3.94 (d), 4.02 (m), (methylamino)pentan-2- 4.24 (d),6.80 (d), 7.04 (m), 7.28 (m) yl)piperidine-1-carboxamide I-320A^(b)(3R)-3-((S)-1-(3-chloro-2- 121 562.1 1.03 (m, 1H), 2.24 (m, 1H), 2.78(s, 3H), fluorophenyl)-1-hydroxy-5- 2.98 (m, 2H), 3.30 (s, 3H), 3.36 (m,2H), methoxypentyl)-N-((S)-3-(4,4- 4.10 (m, 1H), 4.28 (m, 1H), 6.16 (m,1H), difluorocyclohexyl)-1- 7.08 (t, 3H), 7.31 (t, 1H), 7.48 (t, 1H),(methylamino)propan-2- 8.16 (brs, 1H), 9.56 (brs, 1H)yl)piperidine-1-carboxamide I-321A^(b) (3R)-3-((R)-(3-ethoxypropoxy)(3-121 562.2 1.16 (t, 3H), 2.08 (m, 2H), 2.73 (s, 3H),chloro-2-fluorophenyl)methyl)- 2.94 (m, 1H), 3.15 (m, 1H), 3.32 (m, 2H),N-((S)-3-(4,4-difluorocyclohexyl)-1- 3.42 (m, 2H), 3.45 (m, 3H), 3.78(m, 2H), (methylamino)propan-2- 4.16 (m, 2H), 4.34 (d, 1H), 5.79 (m,1H), yl)piperidine-1-carboxamide 7.11 (m, 1H), 7.23 (t, 1H), 7.33 (t,1H), 8.68 (brs, 1H), 10.02 (brs, 1H) I-322A(3R)-3-((S)-1-(3-chlorophenyl)-5- 133 1.53 563, 7.76 (s, 1H), 7.27-7.15(m, 4H), 4.09 (d, methoxy-1-(propionamido)pentyl)- 565 J = 12.9 Hz, 1H),4.05-3.99 (m, 1H), N-((S)-3-cyclohexyl-1- 3.81 (d, J = 11.4 Hz, 1H),3.30 (t, J = 6.3 Hz, (methylamino)propan-2- 2H), 3.01-2.85 (m, 2H), 2.63(s, yl)piperidine-1-carboxamide 3H), 1.08 (t, J = 7.6 Hz, 3H).I-323A^(b) (3R)-N-((S)-3-(4,4- 121 564.3 2.05 (m, 2H), 2.29 (m, 1H),2.72 (s, 3H), difluorocyclohexyl)-1- 3.28 (s, 3H), 3.32 (m, 2H), 3.86(m, 1H), (methylamino)propan-2-yl)-3-((S)-1- 4.25 (m, 2H), 6.11 (m, 2H),6.81 (m, 2H), (2,3,5-trifluorophenyl)-1-hydroxy-5- 7.08 (m, 1H), 8.74(brs, 1H), 9.78 (brs, 1H) methoxypentyl)piperidine-1- carboxamideI-324A^(b) (3R)-3-((R)-(3- 121 564.3 1.08 (t, 3H), 2.73 (s, 3H), 2.99(m, 1H), ethoxypropoxy)(2,3,5- 3.13 (m, 1H), 3.36 (m, 2H), 3.45 (m, 2H),trifluorophenyl)methyl)-N-((S)-3- 3.82 (m, 1H), 4.23 (m, 2H), 4.38 (d,1H), (4,4-difluorocyclohexyl)-1- 5.39 (m, 1H), 6.83 (t, 1H), 7.10 (m,1H), (methylamino)propan-2- 8.70 (brs, 1H), 9.75 (brs, 1H)yl)piperidine-1-carboxamide I-325A (3R)-N-(3-(3,3-difluorocyclobutyl)-1-33 1.55 566 7.40 (m, 3H), 7.10 (d, J = 8.2, 1H),(methylamino)propan-2-yl)-3-((R)-1- 4.42 (d, J = 11.7, 0.5H), 4.31 (d, J= 13.3, hydroxy-5-methoxy-1-(3- 0.5H), 3.99 (m, 1H), 3.91 (d, J = 10.1,(trifluoromethoxy)phenyl)pentyl)piperidine- 0.5H), 3.81 (d, J = 11.3,0.5H), 3.27 (s, 1-carboxamide 3H), 2.68 (s, 3H) I-326A(3R)-3-(1-(3-hydroxypropoxy)-1-(3- 146 1.71 566, not determinedchlorophenyl)-5-methoxypentyl)- 568 N-((S)-3-cyclohexyl-1-(methylamino)propan-2- yl)piperidine-1-carboxamide I-327A^(b)(3R)-N-((S)-1-(2-ethoxyethylamino)- 33 1.71 566 1.10 (m, 3H), 2.75 (m,2H), 3.25 (s, 3H), 3-cyclohexylpropan-2-yl)-3-((S)-1- 3.55 (m, 2H), 3.75(m, 1H), (3-chlorophenyl)-1-hydroxy-5- 7.1-7.40 (m, 4H)methoxypentyl)piperidine-1- carboxamide I-328A(3R)-N-((S)-3-cyclohexyl-1- 33 1.38 567 8.45 (s, 2H), 7.80-7.70 (m, 3H),(methylamino)propan-2-yl)-3-((S)-1- 7.34-7.22 (m, 2H), 6.96-6.88 (dd,1H), 4.09 (m, hydroxy-5-methoxy-1-(2-(pyridin-3- 1H), 3.04 (dd, 1H),2.93-2.82 (m, 1H), yloxy)phenyl)pentyl)piperidine-1- 2.68 (s, 3H), 2.22(td, 1H), 2.11 (tt, 1H). carboxamide I-329A(3R)-3-((R)-1-acetamido-1-(3- 133 1.44 567, 7.90 (s, 1H), 7.31-7.27 (m,1H), chloro-2-fluorophenyl)-5- 569 7.21-7.17 (m, 1H), 7.02 (t, J = 7.9Hz, 1H), methoxypentyl)-N-((S)-3-cyclohexyl- 4.06-3.98 (m, 2H), 3.89 (d,J = 12.9 Hz, 1-(methylamino)propan-2- 1H), 3.24 (t, J = 6.3 Hz, 2H),3.17 (s, yl)piperidine-1-carboxamide 3H), 2.98-2.77 (m, 2H), 2.58 (s,3H), 1.91 (s, 3H). I-329B (3R)-3-((S)-1-acetamido-1-(3- 133 1.46 567,7.98 (s, 1H), 7.32-7.28 (m, 1H), chloro-2-fluorophenyl)-5- 569 7.19-7.15(m, 1H), 7.04 (t, J = 8.1 Hz, 1H), methoxypentyl)-N-((S)-3-cyclohexyl-4.19 (d, J = 9.1 Hz, 1H), 4.03-3.98 (m, 1-(methylamino)propan-2- 1H),3.80 (d, J = 13.2 Hz, 1H), yl)piperidine-1-carboxamide 2.99-2.86 (m,2H), 2.61 (s, 3H), 1.95 (s, 3H). I-330A (3R)-3-((S)-1-(2-(allyloxy)-3-33 1.55 568, 0.96 (d, 3H), 0.99 (d, 3H), 2.70 (s, 3H),bromophenyl)-1-hydroxy-5- 570 3.26 (s, 3H), 3.98 (br d, 1H), 4.08 (br d,methoxypentyl)-N-((S)-4-methyl-1- 1H), 4.30 (br d, 1H), 4.58 (m, 1H),(methylamino)pentan-2- 5.27 (d, 1H), 5.42 (d, 1H), 6.12 (m, 1H),yl)piperidine-1-carboxamide 7.01 (m, 1H), 7.53 (m, 2H) I-331A^(b)(3R)-N-((S)-1-(2,2,2- 118 576.1 1.52 (m, 2H), 2.03 (m, 1H), 2.33 (m,1H), trifluoroethylamino)-3- 2.57 (t, 1H), 3.28 (s, 3H), 3.31 (t, 2H),cyclohexylpropan-2-yl)-3-((S)-1-(3- 3.71 (m, 2H), 3.94 (m, 1H), 4.15 (m,2H), chlorophenyl)-1-hydroxy-5- 5.53 (m, 1H), 7.16 (d, 1H), 7.23 (m,2H), methoxypentyl)piperidine-1- 7.34 (s, 1H) carboxamide I-332A(3R)-3-(1-(3-chlorophenyl)-1- 133 1.55, 577, 7.68, 7.55 (s, 1H),7.18-7.06 (m, 4H), (isobutyramido)-5-methoxypentyl)- 1.59 579 4.03-3.91(m, 2H), 3.78 (d, J = 12.4 Hz, N-((S)-3-cyclohexyl-1- 1H), 3.71 (d, J =12.8 Hz, 1H), 3.127, (methylamino)propan-2- 3.121 (s, 3H), 2.536, 2.522(s, 3H). yl)piperidine-1-carboxamide I-333A^(b)(3R)-3-((S)-5-ethoxy-1-(2,3,5- 121 578.3 1.15 (t, 3H), 2.43 (m, 1H),2.54 (m, 1H), trifluorophenyl)-1-hydroxypentyl)- 2.65 (t, 1H), 2.79 (s,3H), 2.96 (m, 1H), N-((S)-3-(4,4-difluorocyclohexyl)-1- 3.27 (m, 1H),3.36 (t, 2H), 3.45 (t, 2H), (methylamino)propan-2- 3.76 (m, 1H), 4.23(m, 1H), 4.35 (m, 1H), yl)piperidine-1-carboxamide 6.18 (m, 1H), 6.82(m, 1H), 7.09 (m, 1H), 9.01 (brs, 1H), 9.87 (brs, 1H) I-334A^(b)(3R)-N-(5,5,5-trifluoro-4-methyl-1- 33 1.61 580 1.15 (m, 3H), 2.50 (2s,3H), 3.25 (s, 3H), (methylamino)pentan-2-yl)-3-((S)-1- 3.80 (m, 1H),6.77 (d, 1H), 6.95 (m, 2H), hydroxy-5-methoxy-1-(2- 7.10-7.30 (m, 3H),7.35 (m, 2H) phenoxyphenyl)pentyl)piperidine-1- 7.52 (m, 1H) carboxamideI-335A (3R)-3-(1-(2-(benzyloxy)phenyl)-1- 33 1.74 580 7.50-6.89 (m),5.02 (m), 4.15 (d), hydroxy-5-methoxypentyl)-N-((S)-1- 3.96 (m), 3.85(m), 3.21 (m), 3.12 (d), cyclohexyl-3-(methylamino)propan- 2.58 (s),2.51 (s). 2-yl)piperidine-1-carboxamide I-336A(3R)-3-((S)-1-(3-chloro-2- 133 1.52 581 7.99 (s, 0.5H), 7.40 (t, 1H),7.27 (t, 1H), fluorophenyl)-5-methoxy-1- 7.14 (t, 1H), 4.28 (d, 1H),4.11 (m, 1H), (propionamido)pentyl)-N-((S)-3- 3.91 (d, 1H), 3.88 (t,2H), 3.29 (s, 3H), cyclohexyl-1-(methylamino)propan- 3.07 (dd, 1H), 2.71(s, 3H), 2.54 (t, 1H), 2-yl)piperidine-1-carboxamide 1.92 (d, 1H), 1.83(d, 1H), 1.16 (t, 3H). I-337A (3R)-3-((S)-1-(2-(4- 33 1.71 584 0.78-1.76(m), 1.98 (m), 2.30 (m), fluorophenoxy)phenyl)-1-hydroxy-5- 2.62 (m),2.64 (s), 2.86 (m), 3.04 (m), methoxypentyl)-N-((S)-3-cyclohexyl- 3.24(s), 3.26 (t), 4.04 (m), 4.26 (d), 6.64 (d), 1-(methylamino)propan-2-6.96 (m), 7.08-7.20 (m), 7.64 (d) yl)piperidine-1-carboxamide I-338A(3R)-N-((S)-3-cyclohexyl-1- 33 1.74 584 0.78-1.76 (m), 1.96 (m), 2.24(m), (methylamino)propan-2-yl)-3-((S)-1- 2.62 (m), 2.64 (s), 2.86 (m),3.04 (m), (5-fluoro-2-phenoxyphenyl)-1- 3.24 (s), 3.26 (t), 3.98 (d),4.02 (m), 4.24 (d), hydroxy-5- 6.74 (dd), 6.92 (m), 7.14 (m), 7.36 (m),methoxypentyl)piperidine-1- 7.40 (dd) carboxamide I-339A(3R)-3-((S)-1-(2-(2- 33 1.62 594 7.75-7.67 (dd, 2H), 7.59 (br s, 1H),(trifluoromethyl)phenoxy)phenyl)-1- 7.29 (t, 1H), 7.23-7.12 (m, 2H),hydroxy-5-methoxypentyl)-N-((S)-4- 6.99-6.84 (br d, 1H), 6.65 (d, 1H),4.23 (m, methyl-1-(methylamino)pentan-2- 1H), 3.99 (m, 2H), 3.01 (m,1H), yl)piperidine-1-carboxamide 0.99-0.68 (m, 6H). I-340A(3R)-3-((S)-1-(3-chloro-2- 132 1.59 595 7.94 (s, 1H), 7.41 (t, 1H), 7.27(t, 1H), fluorophenyl)-1-(isobutyramido)-5- 7.15 (t, 1H), 4.25 (d, 1H),4.12 (m, 1H), methoxypentyl)-N-((S)-3-cyclohexyl- 3.93 (d, 1H), 3.38 (t,2H), 3.28 (s, 3H), 1-(methylamino)propan-2- 3.08 (dd, 1H), 2.71 (s, 3H),2.54 (t, 1H), yl)piperidine-1-carboxamide 1.13 (dd, 6H). I-340A(3R)-3-((R)-1-(3-chloro-2- 133 1.57 595 7.83 (s, 1H), 7.39 (t, 1H), 7.29(t, 1H), fluorophenyl)-1-(isobutyramido)-5- 7.13 (t, 1H), 4.14 (m, 2H),3.99 (d, 1H), methoxypentyl)-N-((S)-3-cyclohexyl- 3.27 (s, 3H), 3.07(dd, 1H), 2.92 (dd, 1H), 1-(methylamino)propan-2- 2.54 (tm, 1H), 2.03(d, 1H), 1.11 (m, 6H), yl)piperidine-1-carboxamide 1.02 (m, 1H), 0.91(m, 1H). I-341A (3R)-3-((S)-1-(3-chlorophenyl)-1- 121 450 2.53 (m, 2H),2.70 (s, 3H), 2.92 (m, 1H), hydroxypropyl)-N-((S)-1-cyclohexyl- 3.08 (m,1H), 3.96 (m, 1H), 4.12 (m, 3-(methylamino)propan-2- 1H), 4.28 (m, 1H),7.24-7.32 (m, 3H), yl)piperidine-1-carboxamide 7.43 (s, 1H) I-342A(SR)-N-((S)-1-cyclohexyl-3- 37 1.55 460 7.31 (t, 1H), 7.25-7.18 (m, 2H),3.23 (s, (methylamino)propan-2-yl)-2-((RS)- 3H), 2.62 (s, 3H), 2.10 (m,1H), 0.97 (m, 5-methoxy-1- 1H), 0.84 (m, 1H). phenylpentyl)morpholine-4-carboxamide I-343A (3R)-3-((S)-1-(3-chlorophenyl)-1- 121 464 0.88 (t,3H), 2.56 (m, 2H), 2.70 (s, 3H), hydroxybutyl)-N-((S)-1-cyclohexyl- 2.91(m, 1H), 3.06 (m, 1H), 3.98 (m, 3-(methylamino)propan-2- 1H), 4.12 (m,1H), 4.39 (m, 1H), yl)piperidine-1-carboxamide 7.24-7.31 (m, 3H), 7.43(s, 1H) I-345A^(b) 3-((R)-1-cyclohexyl-1-hydroxy-5- 121 473 2.74 (s,3H), 3.28 (s, 3H), 3.09 (m, 1H), methoxypentyl)-N-((S)-1-cyclohexyl-4.64 (m, 1H), 7.40 (m, 2H), 7.71 (m, 3-(methylamino)propan-2- 1H), 8.03(m, 1H), 8.51 (brs, 1H), yl)benzamide 9.18 (brs, 1H) I-346A(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 478 0.86 (t, 3H), 2.53 (m, 2H),2.70 (s, 3H), hydroxypentyl)-N-((S)-1-cyclohexyl- 2.93 (m, 1H), 3.04 (m,1H), 3.96 (d, 3-(methylamino)propan-2- 1H), 4.12 (m, 1H), 4.28 (d, 1H),yl)piperidine-1-carboxamide 7.22-7.31 (m, 3H), 7.43 (s, 1H) I-347A(3R)-3-((R)-1-cyclohexyl-1-hydroxy- 121 480 2.70 (s, 3H), 2.92 (m, 1H),3.06 (m, 1H), 5-methoxypentyl)-N-((S)-1- 3.31 (s, 3H), 4.12 (m, 3H),cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-348A(3R)-3-((S)-1-(3-chlorophenyl)-1,4- 135 1.39 480, 7.37-7.36 (m, 1H),7.26-7.14 (m, 3H), dihydroxybutyl)-N-((S)-1-cyclohexyl- 482 4.22 (d, J =14.6 Hz, 1H), 4.08-4.01 (m, 3-(methylamino)propan-2- 1H), 3.90 (d, J =12.3 Hz, 1H), 3.42 (t, J = 6.3 Hz, yl)piperidine-1-carboxamide 2H), 2.98(dd, J = 12.7, 3.4 Hz, 1H), 2.83 (dd, J = 12.4, 10.4 Hz, 1H), 2.62 (s,3H), 2.50-2.44 (m, 2H), 1.93 (t, J = 8.0 Hz, 2H), 1.75-0.78 (m, 20H).I-349A (3R)-3-((S)-1-(3-chlorophenyl)-1- 117 1.3 485 1.90 (3H, d), 1.00(3H, d), 2.55 (1H, m), hydroxy-5-methoxypentyl)- 2.70 (3H, s), 3.20 (3H,s), 3.90 (1H, d), N-((2R,3S)-3-hydroxy-4-methyl-1- 4.10 (1H, m), 4.35(1H, d), 7.25 (3H, (methylamino)pentan-2- m), 7.40 (1H, m).yl)piperidine-1-carboxamide I-350A (3R)-3-((S)-1-(benzofuran-7-yl)-1- 331.4 488 1.04 (s, 9H), 2.72 (s, 3H), 3.19 (s, 3H),hydroxy-5-methoxypentyl)-N-((S)- 3.99 (br d, 1H), 4.21 (m, 1H), 4.39 (brd, 4,4-dimethyl-1- 1H), 6.82 (d, 1H), 7.20 (m, 1H), 7.41 (d,(methylamino)pentan-2- 1H), 7.52 (d, 1H), 7.68 (d, 1H)yl)piperidine-1-carboxamide I-351A (3R)-3-((S)-1-(2-tert- 121 488 0.84(m, 1H), 1.37 (s, 9H), 2.22 (m, 1H), butylbenzofuran-7-yl)-1-hydroxy-5-2.52 (m, 2H), 2.71 (s, 3H), 3.03 (m, 2H), methoxypentyl)-N-((S)-1- 3.29(s, 3H), 3.92 (m, 1H), 4.01 (m, 1H), (methylamino)propan-2- 4.43 (m,1H), 6.42 (s, 1H), 7.16 (m, 1H), yl)piperidine-1-carboxamide 7.48 (m,2H) I-352A (3R)-N-((2S,3S)-3-amino-1- 121 492 2.62 (m, 1H), 2.80 (m,1H), 3.24 (s, 3H), cyclohexylbutan-2-yl)-3-((S)-1-(2- 3.80 (m, 1H), 3.96(m, 1H), 4.34 (m, fluorophenyl)-1-hydroxy-5- 1H), 6.96 (m, 1H), 7.15 (m,1H), methoxypentyl)piperidine-1- 7.26 (m, 1H), 7.56 (m, 1H) carboxamideI-353A (3R)-N-((1S,2R)-1-cyclopentyl-1- 117 1.29 494 2.60 (1H, m), 2.70(1H, m), 2.85 (3H, s), hydroxy-3-(methylamino)propan-2- 3.24 (3H, s),4.01 (1H, d), 4.45 (1H, d), yl)-3-((S)-1-(3-fluorophenyl)-1- 7.10 (1H,m), 7.25 (2H, m), 7.50 (1H, hydroxy-5- m). methoxypentyl)piperidine-1-carboxamide I-354A (3R)-N-((S)-2-amino-3- 126 1.52 494, 2.43 (m, 1H),2.59 (m, 1H), 3.27 (s, 3H), cyclohexylpropyl)-3-((S)-1-(3- 496 3.90 (brd, 1H), 4.38 (br d, 1H), chlorophenyl)-1-hydroxy-5- 7.20-7.35 (3H), 7.43(s, 1H) methoxypentyl)piperidine-1- carboxamide I-356A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.40 498 1.00 (m), 1.22 (s), 1.24(s), hydroxy-5-methoxypentyl)-N-((S)-4- 1.26-1.98 (m), 2.44 (dd), 2.56(dd), 2.70 (s), methoxy-4-methyl-1- 2.98 (dd), 3.18 (dd), 3.22 (s), 3.26(s), (methylamino)pentan-2- 3.32 (t), 3.88 (d), 4.18 (m), 4.36 (d),yl)piperidine-1-carboxamide 7.24 (m), 7.42 (s) I-357A(3R)-3-((S)-1-(3-cyanophenyl)-1- 139 1.40 499 0.84-1.10 (m), 1.18-2.06(m), 2.54 (m), hydroxy-5-methoxypentyl)-N-((S)-1- 2.72 (s), 2.94 (dd),3.06 (dd), 3.24 (s), cyclohexyl-3-(methylamino)propan- 3.30 (t), 3.98(d), 4.14 (m), 4.34 (d), 2-yl)piperidine-1-carboxamide 7.56 (dd), 7.62(d), 7.68 (d), 7.78 (s) I-358A (3R)-3-((R)-1-(3-chloro-2- 121 500 0.83(m, 1H), 0.98 (s, 9H), 1.95 (m, 2H), fluorophenyl)-1-hydroxy-5- 2.22 (m,1H), 2.70 (s, 3H), 2.91 (m, 1H), methoxypentyl)-N-((S)-4,4-dimethyl-3.03 (m, 1H), 3.27 (s, 3H), 3.82 (d, 1H), 1-(methylamino)pentan-2- 4.21(m, 1H), 4.52 (d, 1H), 7.14 (m, yl)piperidine-1-carboxamide 1H), 7.38(m, 1H), 7.54 (m, 1H) I-359A (3R)-3-((S)-1-(2-chloro-3- 119 500 0.74 (m,1H), 1.00 (s, 9H), 1.92 (m, 1H), fluorophenyl)-1-hydroxy-5- 2.46 (m,1H), 2.71 (s, 3H), 2.92 (m, 2H), methoxypentyl)-N-((S)-4,4-dimethyl-3.04 (m, 1H), 3.25 (s, 3H), 4.02 (d, 2H), 1-(methylamino)pentan-2- 4.18(m, 1H), 4.32 (d, 1H), 7.14 (m, yl)piperidine-1-carboxamide 1H), 7.28(m, 1H), 7.58 (m, 1H) I-360A (3R)-3-((S)-1-(3-chloro-2- 117 1.32 5031.90 (3H, d), 1.00 (3H, d), 2.55 (1H, m), fluorophenyl)-1-hydroxy-5-2.70 (3H, s), 3.25 (3H, s), 3.90 (1H, d), methoxypentyl)-N-((2R,3S)-3-4.10 (1H, m), 4.30 (1H, d), 7.10 (1H, hydroxy-4-methyl-1- m), 7.35 (1H,m), 7.55 (1H, m). (methylamino)pentan-2- yl)piperidine-1-carboxamideI-361A (3R)-3-((S)-1-(benzo[b]thiophen-4- 33 1.52 504 0.92 (s, 9H), 2.85(s, 3H), 3.15 (s, 3H), yl)-1-hydroxy-5-methoxypentyl)- 3.90 (br d, 1H),4.12 (s, 1H), 4.30 (br d, N-((S)-4,4-dimethyl-1- 1H), 7.24 (t, 1H), 7.40(m, 1H), 7.48 (d, (methylamino)pentan-2- 1H), 7.75 (m, 2H)yl)piperidine-1-carboxamide I-362A (3R)-3-((S)-4-acetamido-1-(2- 121 5050.88 (m, 1H), 1.02 (m, 2H), 1.82 (m, fluorophenyl)-1-hydroxybutyl)- 1H),1.87 (s, 3H), 1.96 (m, 2H), 2.16 (m, N-((S)-1-cyclohexyl-3- 1H), 2.64(m, 1H), 2.71 (d, 3H), (methylamino)propan-2- 2.80 (m, 1H), 2.95 (m,1H), 3.08 (m, 3H), yl)piperidine-1-carboxamide 4.00 (d, 1H), 4.14 (m,1H), 4.32 (d, 1H), 7.00 (m, 1H), 7.16 (m, 1H), 7.26 (m, 1H), 7.58 (m,1H) I-363A (3R)-N-((S)-1-cyclohexyl-3- 121 506 0.88 (m, 1H), 1.96 (m,2H), 2.32 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 2.69 (s, 3H),3.02 (m, 1H), 3.25 (s, 3H), (3-fluoro-2-methylphenyl)-1- 3.99 (d, 1H),4.14 (m, 1H), 4.27 (d, 1H), hydroxy-5- 4.64 (s, 1H), 6.92 (m, 1H), 7.14(m, 1H), methoxypentyl)piperidine-1- 7.34 (m, 1H) carboxamide I-363B(3R)-N-((S)-1-cyclohexyl-3- 121 506 0.88 (m, 1H), 2.01 (m, 1H), 2.32 (s,3H), (methylamino)propan-2-yl)-3-((R)-1- 2.73 (s, 3H), 2.89 (m, 1H),3.06 (m, 1H), (3-fluoro-2-methylphenyl)-1- 3.26 (s, 3H), 3.82 (d, 1H),4.15 (m, 1H), hydroxy-5- 4.49 (d, 1H), 6.93 (m, 1H), 7.12 (m,methoxypentyl)piperidine-1- 1H), 7.34 (m, 1H) carboxamide I-364A(3R)-N-((S)-1-cyclohexyl-3- 121 506 2.24 (s, 3H), 2.50 (m, 2H), 2.69 (s,3H), (methylamino)propan-2-yl)-3-((S)-1- 2.92 (m, 1H), 3.05 (m, 1H),3.27 (s, 3H), (3-fluoro-4-methylphenyl)-1- 3.97 (d, 1H), 4.12 (m, 1H),4.36 (d, 1H), hydroxy-5- 7.05 (m, 2H), 7.17 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-364B(3R)-N-((S)-1-cyclohexyl-3- 121 506 2.23 (s, 3H), 2.50 (m, 2H), 2.69 (s,3H), (methylamino)propan-2-yl)-3-((R)-1- 2.88 (m, 1H), 3.06 (m, 1H),3.27 (s, 3H), (3-fluoro-4-methylphenyl)-1- 3.96 (d, 1H), 4.12 (m, 1H),4.27 (d, 1H), hydroxy-5- 7.04 (m, 2H), 7.18 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-366A(3R)-N-((S)-1-cyclohexyl-3- 121 508 0.88 (m, 1H), 2.22 (m, 1H), 2.70 (s,3H), (methylamino)propan-2-yl)-3-((S)-1- 2.94 (m, 1H), 3.06 (m, 1H),3.26 (s, 3H), (3-fluoro-2-hydroxyphenyl)-1- 3.94 (d, 1H), 4.14 (m, 1H),4.34 (d, 1H), hydroxy-5- 6.76 (m, 1H), 6.95 (m, 2H)methoxypentyl)piperidine-1- carboxamide I-367A(3R)-N-((1S,2R)-1-cyclohexyl-1- 121 508 0.86 (m, 1H), 2.17 (m, 1H), 2.64(m, hydroxy-3-(methylamino)propan-2- 1H), 2.71 (s, 3H), 2.78 (m, 1H),3.04 (m, yl)-3-((S)-1-(2-fluorophenyl)-1- 1H), 3.24 (s, 3H), 3.46 (m,1H), 3.96 (m, hydroxy-5- 1H), 4.10 (m, 1H), 4.34 (m, 1H),methoxypentyl)piperidine-1- 7.01 (m, 1H), 7.16 (m, 1H), 7.27 (m, 1H),carboxamide 7.56 (m, 1H) I-368A (3R)-N-((2S,3R)-3-amino-1- 119 508 1.24(s, 3H), 2.54 (m, 2H), 3.26 (s, 3H), cyclohexylbutan-2-yl)-3-((S)-1-(3-3.96 (d, 1H), 4.08 (m, 1H), 4.34 (d, 1H), chlorophenyl)-1-hydroxy-5-7.24 (m, 3H), 7.43 (s, 1H) methoxypentyl)piperidine-1- carboxamideI-369A (3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.53 508 7.43 (s, 1H),7.32-7.25 (m, 2H), 7.21 (d, hydroxy-5-methoxypentyl)-N-((S)-3- 1H), 4.37(d, 1H), 3.89 (d, 1H), 3.51 (d, cyclohexyl-2- 1H), 2.72 (s, 3H), 2.59(t, 1H), 2.45 (t, (methylamino)propyl)piperidine-1- 1H), 1.93 (t, 1H),0.99 (m, 1H). carboxamide I-370A (3R)-N-((S)-1-(cis-4- 119 510 0.85 (m,1H), 2.15 (m, 1H), 2.77 (s, 1H), fluorocyclohexyl)-3- 2.81 (m, 1H), 2.93(m, 1H), 3.07 (m, (methylamino)propan-2-yl)-3-((S)-1- 1H), 3.24 (s, 3H),3.98 (d, 1H), 4.15 (m, (2-fluorophenyl)-1-hydroxy-5- 1H), 4.33 (d, 1H),6.99 (m, 1H), methoxypentyl)piperidine-1- 7.16 (m, 1H), 7.28 (m, 1H),7.60 (m, 1H) carboxamide I-370B (3R)-N-((S)-1-(trans-4- 119 510 0.88 (m,1H), 2.62 (m, 1H), 2.70 (s, 3H), fluorocyclohexyl)-3- 2.84 (m, 2H), 3.06(m, 1H), 3.25 (s, 3H), (methylamino)propan-2-yl)-3-((S)-1- 3.98 (m, 1H),4.10 (m, 1H), 4.34 (m, (2-fluorophenyl)-1-hydroxy-5- 1H), 7.00 (m, 1H),7.17 (m, 1H), methoxypentyl)piperidine-1- 7.38 (m, 1H), 7.59 (m, 1H)carboxamide I-370C (3R)-N-((S)-1-(trans-4- 119 510 0.86 (m, 1H), 2.64(m, 1H), 2.7 (s, 3H), fluorocyclohexyl)-3- 2.85 (m, 2H), 3.06 (m, 1H),3.26 (s, 3H), (methylamino)propan-2-yl)-3-((R)-1- 4.04 (m, 2H), 4.42 (m,2H), 7.02 (m, (2-fluorophenyl)-1-hydroxy-5- 1H), 7.15 (m, 2H), 7.26 (m,2H), methoxypentyl)piperidine-1- 7.56 (m, 1H) carboxamide I-371A(3R)-N-((1S,2R)-1-cyclopentyl-1- 117 1.3 512 3.05 (3H, s), 3.75 (3H, s),4.35 (1H, m), hydroxy-3-(methylamino)propan-2- 4.75 (1H, m), 7.50 (2H,m), 7.75 (1H, yl)-3-((S)-1-(2,3-difluorophenyl)-1- m). hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-372A(3R)-3-((S)-1-(2-chloro-3- 121 512 0.74 (m, 1H), 1.00 (m, 1H), 2.46 (m,fluorophenyl)-1-hydroxy-5- 1H), 2.71 (s, 3H), 2.93 (m, 2H), 3.12 (m,methoxypentyl)-N-((S)-1- 1H), 3.25 (s, 3H), 4.04 (m, 2H), 4.33 (m,cyclopentyl-3-(methylamino)propan- 1H), 7.12 (m, 1H), 7.26 (m, 1H),2-yl)piperidine-1-carboxamide 7.59 (m, 1H), I-373A(3R)-N-((S)-2-amino-3- 127 1.53 512, 2.68 (m, 2H), 3.88 (br d, 1H), 4.41(br d, cyclohexylpropyl)-3-((S)-1-(3- 514 1H), 7.13 (t, 1H), 7.37 (m,1H), 7.53 (m, chloro-2-fluorophenyl)-1-hydroxy-5- 1H)methoxypentyl)piperidine-1- carboxamide I-374A(3R)-3-((S)-1-(benzofuran-4-yl)-1- 33 1.53 514 2.69 (s, 3H), 3.92 (br d,1H), 4.12 (m, hydroxy-5-methoxypentyl)-N-((S)-1- 1H), 4.39 (br d, 1H),7.10 (s, 1H), cyclohexyl-3-(methylamino)propan- 7.24 (m, 2H), 7.39 (m,1H), 7.72 (s, 1H) 2-yl)piperidine-1-carboxamide I-375A(3R)-3-((S)-4-acetamido-1-(3,5- 121 515 0.90 (m, 1H), 1.02 (m, 1H), 2.30(s, 6H), dimethylphenyl)-1-hydroxybutyl)- 2.55 (m, 2H), 2.71 (s, 3H),3.98 (d, 1H), N-((S)-1-cyclohexyl-3- 4.13 (m, 1H), 4.22 (d, 1H), 6.86(s, 1H), (methylamino)propan-2- 6.97 (s, 2H) yl)piperidine-1-carboxamideI-376A (3R)-3-((R)-1-cyclohexyl-1-hydroxy- 121 516 2.04 (m, 2H), 2.72(s, 3H), 3.32 (s, 3H), 5-methoxypentyl)-N-((S)-1-(4,4- 4.14 (m, 3H)difluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-377A (3R)-N-((S)-2-amino-3- 127 1.53 5163.18 (s, 3H), 3.83 (br d, 1H), 4.48 (br d, cyclohexylpropyl)-3-((S)-1-1H), 7.30 (t, 1H), 7.45 (m, 1H), 7.55 (d,(benzo[b]thiophen-4-yl)-1-hydroxy- 1H), 7.80 (m, 2H)5-methoxypentyl)piperidine-1- carboxamide I-378A(3R)-3-((S)-1-(3-chloro-2- 33 1.43 516 0.82 (m), 1.22 (s), 1.24 (s),fluorophenyl)-1-hydroxy-5- 1.26-2.04 (m), 2.18 (m), 2.62 (m), 2.72 (s),methoxypentyl)-N-((S)-4-methoxy- 2.98 (dd), 3.18 (dd), 3.22 (s), 3.24(s), 4-methyl-1-(methylamino)pentan-2- 3.30 (t), 3.86 (d), 4.18 (m),4.38 (d), yl)piperidine-1-carboxamide 7.16 (dd), 7.38 (dd), 7.54 (dd)I-379A (3R)-3-((S)-1-(2-cyano-5- 140 1.09 517 0.83-1.10 (m), 1.14-1.82(m), 2.24 (m), fluorophenyl)-1-hydroxy-5- 2.32 (m), 2.44 (m), 2.72 (s),2.98 (dd), methoxypentyl)-N-((S)-1-cyclohexyl- 3.06 (d), 3.24 (s), 3.32(t), 3.96 (d), 3-(methylamino)propan-2- 4.14 (m), 4.40 (d), 7.62 (m),8.32 (m) yl)piperidine-1-carboxamide I-380A(3R)-3-((S)-1-(3-carbamoylphenyl)- 33 1.20 517 0.82-2.06 (m), 2.50 (m),2.70 (s), 1-hydroxy-5-methoxypentyl)-N-((S)- 2.96 (dd), 3.04 (d), 3.24(s), 3.32 (t), 3.98 (d), 1-cyclohexyl-3- 4.12 (m), 4.32 (d), 7.42 (m),7.58 (d), (methylamino)propan-2- 7.74 (d), 7.94 (s)yl)piperidine-1-carboxamide I-381A (RS)-N-((S)-2-amino-3- 127 1.47 5182.60 (t, 1H), 2.82 (m, 1H), 3.22 (s, 3H), cyclohexylpropyl)-2-((RS)-1-4.09 (d, 1H), 7.28-7.56 (4H), 7.72 (d,(benzo[b]thiophen-7-yl)-1-hydroxy- 1H) 5-methoxypentyl)morpholine-4-carboxamide I-382A (3R)-3-((S)-4-acetamido-1-(3-fluoro- 121 519 0.88 (m,1H), 1.04 (m, 1H), 1.89 (s, 3H), 5-methylphenyl)-1-hydroxybutyl)- 2.34(s, 3H), 2.54 (m, 2H), 2.70 (s, 3H), N-((S)-1-cyclohexyl-3- 2.92 (m,1H), 3.96 (d, 1H), 4.14 (m, (methylamino)propan-2- 1H), 4.36 (d, 1H),6.76 (d, 1H), 6.94 (d, yl)piperidine-1-carboxamide 1H), 6.98 (s, 1H)I-383A (3R)-3-((S)-4-acetamido-1-(2-fluoro- 121 519 1.12 (m, 3H), 1.97(s, 3H), 2.41 (s, 3H), 5-methylphenyl)-1-hydroxybutyl)- 2.72 (m, 1H),2.80 (s, 3H), 2.94 (m, 2H), N-((S)-1-cyclohexyl-3- 3.17 (m, 3H), 4.10(d, 1H), 4.13 (m, (methylamino)propan-2- 1H), 4.36 (d, 1H), 6.97 (m,1H), yl)piperidine-1-carboxamide 7.15 (m, 1H), 7.48 (m, 1H) I-385A(3R)-3-(1-(2-(cyclopropylmethoxy)- 121 522 0.78 (m, 1H), 0.94 (d, 3H),0.98 (d, 3H), 3-fluorophenyl)-1-hydroxy-5- 1.14 (m, 1H), 1.86 (m, 1H),2.62 (m, methoxypentyl)-N-((S)-4-methyl-1- 1H), 2.71 (s, 3H), 2.90 (m,2H), 3.08 (m, (methylamino)pentan-2- 1H), 3.26 (s, 3H), 4.04 (m, 2H),4.28 (m, yl)piperidine-1-carboxamide 1H), 4.46 (m, 1H), 6.95 (m, 2H),7.28 (m, 1H), I-386A (3R)-3-((S)-1-(3-chloro-2- 121 522 0.86 (m, 1H),2.24 (m, 1H), 2.47 (s, 3H), methylphenyl)-1-hydroxy-5- 2.65 (s, 3H),2.92 (m, 2H), 3.05 (m, 1H), methoxypentyl)-N-((S)-1-cyclohexyl- 3.25 (s,3H), 3.96 (d, 1H), 4.12 (m, 1H), 3-(methylamino)propan-2- 4.29 (d, 1H),7.11 (m, 1H), 7.28 (m, yl)piperidine-1-carboxamide 1H), 7.54 (m, 1H)I-386B (3R)-3-((R)-1-(3-chloro-2- 121 522 0.88 (m, 1H), 2.06 (m, 1H),2.32 (m, methylphenyl)-1-hydroxy-5- 1H), 2.47 (s, 3H), 2.72 (s, 3H),2.90 (m, methoxypentyl)-N-((S)-1-cyclohexyl- 1H), 3.06 (m, 1H), 3.25 (s,3H), 3.84 (d, 3-(methylamino)propan-2- 1H), 4.16 (m, 1H), 4.48 (d, 1H),yl)piperidine-1-carboxamide 7.12 (m, 1H), 7.26 (m, 1H), 7.55 (m, 1H)I-387A (3R)-3-((S)-1-(3-chlorophenyl)-1,5- 33 1.68 522, 7.27-7.15 (m,4H), 4.18 (d, J = 13.2 Hz, dimethoxypentyl)-N-((S)-1- 524 1H), 4.02-3.95(m, 1H), 3.86 (d, J = 12.6 Hz, cyclohexyl-3-(methylamino)propan- 1H),3.30 (t, J = 6.3 Hz, 2H), 2-yl)piperidine-1-carboxamide 3.19 (s, 3H),3.07 (s, 3H), 2.93 (dd, J = 12.6, 2.6 Hz, 1H), 2.80 (dd, J = 12.3, 10.2Hz, 1H), 2.57 (s, 3H), 2.23-0.72 (m, 26H). I-388A(3R)-3-((S)-4-acetamido-1-(2,3- 33 1.3 523 7.30-7.25 (m, 1H), 7.10-7.00(m, 2H), difluorophenyl)-1-hydroxybutyl)- 4.23 (d, J = 12.3 Hz, 1H),4.08-4.01 (m, N-((S)-1-cyclohexyl-3- 1H), 3.90 (d, J = 12.6 Hz, 1H),(methylamino)propan-2- 3.02-2.95 (m, 3H), 2.84 (dd, J = 12.6, 10.2 Hz,yl)piperidine-1-carboxamide 1H), 2.71 (t, J = 12.3 Hz, 1H), 2.61 (s,3H), 2.56-2.50 (m, 1H), 1.79 (s, 3H), 2.08-0.76 (m, 22H). I-389A(3R)-3-((S)-4-acetamido-1-(3,5- 121 523 0.90 (m, 2H), 1.90 (s, 3H), 2.56(m, 1H), difluorophenyl)-1-hydroxybutyl)- 2.70 (s, 3H), 2.92 (m, 2H),3.96 (d, 1H), N-((S)-1-cyclohexyl-3- 4.14 (m, 1H), 4.29 (d, 1H), 6.82(m, (methylamino)propan-2- 1H), 6.98 (m, 2H),yl)piperidine-1-carboxamide I-390A (3R)-3-((S)-1-(2,3-difluorophenyl)-1-33 1.59 524 7.33 (t), 7.11 (m), 4.31 (d), 4.06 (m),hydroxy-5-methoxypentyl)-N-((S)-1- 3.95 (d), 3.27 (m), 3.26 (m), 3.05(t), (methylamino)-3-(4- 2.90 (t), 2.78 (t), 2.69 (s), 2.60 (t),methylcyclohexyl)propan-2- 0.92 (d), 0.88 (d)yl)piperidine-1-carboxamide I-391A (3R)-3-((S)-1-(3-chlorophenyl)-1- 121524 1.02 (m, 3H), 2.52 (m, 2H), 2.70 (s, 3H),hydroxy-5-methoxypentyl)-N-((S)-1- 2.92 (m, 1H), 3.04 (m, 1H), 3.29 (s,3H), (cis-4-hydroxycyclohexyl)-3- 3.46 (m, 1H), 3.96 (d, 1H), 4.11 (m,(methylamino)propan-2- 1H), 4.32 (d, 1H), 7.36 (m, 3H),yl)piperidine-1-carboxamide 7.45 (m, 1H) I-391A(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 524 1.02 (m, 1H), 2.50 (m, 2H),2.70 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.94 (m, 1H), 3.06 (m,1H), 3.26 (s, 3H), (trans-4-hydroxycyclohexyl)-3- 3.94 (m, 2H), 4.12 (m,1H), 4.30 (m, (methylamino)propan-2- 1H), 7.28 (m, 3H), 7.44 (m, 1H)yl)piperidine-1-carboxamide I-392A (3R)-3-((S)-4-acetamido-1-(2,3- 1171.16 525 1.89 (3H, s), 2.73 (3H, s), 3.95 (1H, d)difluorophenyl)-1-hydroxybutyl)- 4.00 (1H, m), 4.36 (1H, d), 7.14 (2H,N-((2R)-1-cyclopentyl-1-hydroxy-3- m), 7.36 (1H, m).(methylamino)propan-2- yl)piperidine-1-carboxamide I-393A(3R)-3-((S)-(2-acetamidoethoxy)(3- 121 525 0.86 (m, 1H), 0.96 (m, 1H),1.94 (s, 3H), chloro-2-fluorophenyl)methyl)- 2.68 (s, 3H), 3.04 (m, 1H),3.82 (d, 1H), N-((S)-1-cyclohexyl-3- 3.94 (d, 1H), 4.06 (m, 1H), 4.56(m, (methylamino)propan-2- 1H), 7.22 (m, 1H), 7.48 (m, 2H)yl)piperidine-1-carboxamide I-393B (3R)-3-((R)-(2-acetamidoethoxy)(3-121 525 0.88 (m, 1H), 1.04 (m, 1H), 1.94 (s, 3H),chloro-2-fluorophenyl)methyl)- 2.70 (s, 3H), 2.95 (m, 2H), 3.12 (m, 2H),N-((S)-1-cyclohexyl-3- 3.78 (d, 1H), 4.06 (d, 1H), 4.14 (m, 1H),(methylamino)propan-2- 4.45 (m, 1H), 7.22 (m, 1H), 7.34 (m,yl)piperidine-1-carboxamide 1H), 7.44 (m, 1H) I-394A(3R)-N-((R)-2-amino-3-tert- 127 1.43 502 7.53 (t, 1H), 7.36 (t, 1H),7.13 (t, 1H), butoxypropyl)-3-((S)-1-(3-chloro-2- 4.40 (d, 1H), 3.86 (d,1H), 3.61 (dd, 1H), fluorophenyl)-1-hydroxy-5- 3.49 (m, 1H), 3.40 (s,3H), 3.25 (s, 3H), methoxypentyl)piperidine-1- 2.69 (q, 2H), 2.19 (tt,1H), 1.61 (d, 1H), carboxamide 1.24 (s, 9H), 0.83 (m, 1H). I-395A(3R)-N-((1S,2R)-1-cyclohexyl-1- 117 1.40 526 0.86 (m), 1.04-2.04 (m),2.18 (m), hydroxy-3-(methylamino)propan-2- 2.64 (m), 2.72 (s), 2.78 (m),3.04 (dd), yl)-3-((S)-1-(2,3-difluorophenyl)-1- 3.24 (s), 3.32 (t), 3.42(m), 3.84, 3.98 (d), hydroxy-5- 4.12 (m), 4.36, 4.48 (d), 7.16 (m),methoxypentyl)piperidine-1- 7.38 (m) carboxamide I-396A(3R)-3-((S)-1-(2,3-difluorophenyl)-1- 121 526 1.75 (m, 1H), 2.16 (m,1H), 2.70 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.95 (m, 1H), 3.06(m, 1H), 3.48 (m, (cis-4-hydroxycyclohexyl)-3- 1H), 3.96 (d, 1H), 4.12(m, 1H), 4.35 (d, (methylamino)propan-2- 1H), 7.15 (m, 2H), 7.36 (m, 1H)yl)piperidine-1-carboxamide I-396B (3R)-3-((S)-1-(2,3-difluorophenyl)-1-121 526 0.86 (m, 1H), 2.15 (m, 1H), 2.64 (m,hydroxy-5-methoxypentyl)-N-((S)-1- 1H), 2.70 (s, 3H), 2.78 (m, 1H), 2.94(m, (trans-4-hydroxycyclohexyl)-3- 1H), 3.06 (m, 1H), 3.25 (s, 3H), 3.96(m, (methylamino)propan-2- 2H), 4.14 (m, 1H), 4.34 (m, 1H),yl)piperidine-1-carboxamide 7.15 (m, 2H), 7.36 (m, 1H) I-397A(3R)-N-((1S,2R)-1-cyclohexyl-1- 121 526 0.88 (m, 1H), 1.96 (m, 2H), 2.15(m, hydroxy-3-(methylamino)propan-2- 1H), 2.64 (m, 1H), 2.71 (s, 3H),2.78 (m, yl)-3-((S)-1-(2,5-difluorophenyl)-1- 1H), 3.05 (m, 1H), 3.26(m, 3H), hydroxy-5- 3.44 (m, 1H), 3.96 (d, 1H), 4.08 (m, 1H),methoxypentyl)piperidine-1- 4.32 (d, 1H), 7.00 (m, 2H), 7.32 (m, 1H)carboxamide I-398A (3R)-3-((S)-1-(2-chloro-3- 121 526 0.75 (m, 1H), 2.46(m, 1H), 2.64 (m, fluorophenyl)-1-hydroxy-5- 2H), 2.71 (s, 3H), 2.95 (m,2H), 3.04 (m, methoxypentyl)-N-((S)-1-cyclohexyl- 1H), 3.24 (s, 3H),4.00 (d, 1H), 4.12 (m, 3-(methylamino)propan-2- 1H), 4.32 (d, 1H), 7.14(m, 1H), yl)piperidine-1-carboxamide 7.29 (m, 1H), 7.59 (m, 1H) I-399A(3R)-N-((2S,3R)-3-amino-1- 119 526 0.84 (m, 1H), 1.98 (m, 2H), 2.16 (m,cyclohexylbutan-2-yl)-3-((S)-1-(3- 1H), 2.64 (m, 1H), 2.34 (m, 1H), 3.26(s, chloro-2-fluorophenyl)-1-hydroxy-5- 3H), 4.00 (d, 1H), 4.08 (m, 1H),4.36 (d, methoxypentyl)piperidine-1- 1H), 7.15 (m, 1H), 7.38 (m, 1H),carboxamide 7.53 (m, 1H) I-400A (3R)-N-((S)-1-cyclohexyl-3- 121 528 0.88(m, 1H), 1.04 (m, 1H), 1.94 (m, (methylamino)propan-2-yl)-3-((S)-1- 2H),2.12 (m, 1H), 2.64 (m, 1H), 2.71 (s, hydroxy-5-methoxy-1-(2,3,4- 3H),2.78 (m, 1H), 2.94 (m, 1H), trifluorophenyl)pentyl)piperidine-1- 3.06(m, 1H), 3.29 (s, 3H), 3.97 (d, 1H), carboxamide 4.14 (m, 1H), 4.34 (d,1H), 7.08 (m, 1H), 7.37 (m, 1H) I-401A (3R)-N-((S)-1-(4,4- 121 528 2.71(s, 3H), 2.80 (m, 1H), 2.94 (m, 1H), difluorocyclohexyl)-3- 3.06 (m,1H), 3.27 (s, 3H), 3.96 (d, 1H), (methylamino)propan-2-yl)-3-((S)-1-4.14 (m, 1H), 4.32 (d, 1H), 7.00 (m, (2-fluorophenyl)-1-hydroxy-5- 1H),7.16 (m, 1H), 7.28 (m, 1H), methoxypentyl)piperidine-1- 7.60 (m, 1H)carboxamide I-402A (3R)-3-((S)-1-(2,5-difluorophenyl)-1- 119 528 0.86(m, 1H), 2.72 (s, 3H), 3.06 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-1-3.23 (s, 3H), 3.96 (d, 1H), 4.14 (m, 1H), (cis-4-fluorocyclohexyl)-3-4.32 (d, 1H), 7.01 (m, 2H), 7.32 (m, 1H) (methylamino)propan-2-yl)piperidine-1-carboxamide I-402B (3R)-3-((S)-1-(2,5-difluorophenyl)-1-119 528 0.86 (m, 1H), 1.80 (m, 1H), 2.62 (m,hydroxy-5-methoxypentyl)-N-((S)-1- 1H), 2.71 (s, 3H), 2.84 (m, 2H), 3.25(s, (trans-4-fluorocyclohexyl)-3- 3H), 3.96 (m, 1H), 4.12 (m, 1H),(methylamino)propan-2- 4.34 (m, 1H), 4.94 (m, 1H), 7.02 (m, 2H),yl)piperidine-1-carboxamide 7.30 (m, 1H) I-403A(3R)-3-((S)-1-(2,3-difluorophenyl)-1- 119 528 2.64 (m, 1H), 2.71 (s,3H), 2.78 (m, 1H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.94 (m, 1H), 3.06(m, 1H), 3.25 (s, 3H), (trans-4-fluorocyclohexyl)-3- 3.96 (m, 1H), 4.12(m, 1H), 4.40 (m, (methylamino)propan-2- 2H), 7.15 (m, 2H), 7.36 (m, 1H)yl)piperidine-1-carboxamide I-403B (3R)-3-((R)-1-(2,3-difluorophenyl)-1-119 528 2.64 (m, 1H), 2.70 (s, 3H), 2.86 (m, 2H),hydroxy-5-methoxypentyl)-N-((S)-1- 3.05 (m, 1H), 3.25 (m, 3H), 3.96 (m,(trans-4-fluorocyclohexyl)-3- 1H), 4.10 (m, 1H), 4.35 (m, 1H),(methylamino)propan-2- 4.50 (m, 1H), 7.14 (m, 2H), 7.36 (m, 1H)yl)piperidine-1-carboxamide I-404A 2-((R)-1-(3-chloro-2-fluorophenyl)-1-33 1.47 528 7.53 (t, 1H), 7.36 (t, 1H), 7.13 (t, 1H),hydroxy-5-methoxypentyl)-N-((S)-1- 3.82 (q, 3H), 3.71 (d, 1H), 3.42 (q,2H), cyclohexyl-3-(methylamino)propan- 3.27 (s, 3H), 2.71 (s, 3H), 2.10(q, 2-yl)morpholine-4-carboxamide 1H) 1.03 (m, 1H). I-405A(3R)-3-((S)-1-(3-chloro-2- 117 1.36 528 3.00 (3H, s), 3.55 (3H, s), 4.25(1H, d), fluorophenyl)-1-hydroxy-5- 4.37 (1H, m), 4.70 (1H, d), 7.40(1H, m), methoxypentyl)-N-((1S,2R)-1- 7.70 (1H, m), 7.85 (1H, m).cyclopentyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-406A (3R)-3-((S)-1-(3-chloro-2- 33 1.26528 2.72 (3H, s), 3.25 (3H, s), 3.40 (4H, m), fluorophenyl)-1-hydroxy-5-4.84 (1H, d), 7.14 (1H, m), 7.38 (1H, methoxypentyl)-N-((S)-1- m), 7.53(1H, m). (methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1- carboxamide I-406B(3R)-3-((S)-1-(3-chloro-2- 33 1.26 526 2.71 (3H, s), 3.20 (3H, s), 3.40(4H, m), fluorophenyl)-1-hydroxy-5- 4.50 (1H, d), 7.14 (1H, m), 7.37(1H, methoxypentyl)-N-((R)-1- m), 7.53 (1H, m).(methylamino)-3-(tetrahydro-2H- pyran-4-yl)propan-2-yl)piperidine-1-carboxamide I-408A (3R)-3-((S)-1-(benzo[b]thiophen-4- 33 1.64 530 2.64(s, 3H), 3.13 (s, 3H), 3.90 (br d, yl)-1-hydroxy-5-methoxypentyl)- 1H),4.34 (br d, 1H), 7.24 (t, 1H), N-((S)-1-cyclohexyl-3- 7.40 (m, 1H), 7.47(d, 1H), 7.75 (m, 2H) (methylamino)propan-2- yl)piperidine-1-carboxamideI-410A (3R)-3-((S)-1-(benzofuran-7-yl)-1- 119 532 0.74 (m, 1H), 2.26 (m,1H), 2.46 (m, hydroxy-5-methoxypentyl)-N-((S)-1- 1H), 2.72 (s, 3H), 2.78(m, 1H), 2.93 (m, (cis-4-fluorocyclohexyl)-3- 1H), 3.07 (m, 1H), 3.21(s, 3H), 3.96 (m, (methylamino)propan-2- 1H), 4.15 (m, 1H), 4.42 (m,1H), yl)piperidine-1-carboxamide 4.75 (m, 1H), 6.84 (m, 1H), 7.24 (m,1H), 7.41-7.53 (m, 2H), 7.72 (m, 1H) I-411A (3R)-N-((S)-1-cyclohexyl-3-33 1.6 532 2.71 (s, 3H), 3.20 (s, 3H), 3.24 (t, 2H),(methylamino)propan-2-yl)-3-((S)-1- 4.00 (br d, 1H), 4.15 (m, 1H), 4.40(br d, (2-fluorobenzofuran-7-yl)-1- 1H), 6.03 (d, 1H), 7.22 (m, 1H),hydroxy-5- 7.41 (m, 2H) methoxypentyl)piperidine-1- carboxamide I-412Amethyl 3-((S)-1-((R)-1-((S)-1- 141 1.44 532 0.84-1.14 (m), 1.18-2.06(m), 2.54 (m), cyclohexyl-3-(methylamino)propan- 2.70 (s), 2.93 (dd),3.04 (dd), 3.24 (s), 2-ylcarbamoyl)piperidin-3-yl)-1- 3.30 (t), 3.92(s), 3.98 (d), 4.14 (m), hydroxy-5-methoxypentyl)benzoate 4.32 (d), 7.44(dd), 7.62 (d), 7.90 (d), 8.06 (s) I-413A(RS)-2-((RS)-1-(benzo[b]thiophen- 33 1.52 532 2.65 (s, 3H), 3.21 (s,3H), 7-yl)-1-hydroxy-5-methoxypentyl)- 7.28-7.52 (4H), 7.72 (m, 1H)N-((S)-1-cyclohexyl-3- (methylamino)propan-2-yl)morpholine-4-carboxamide I-416A (3R)-3-((S)-1-(3-chlorophenyl)-1- 331.38 535, 7.33-7.32 (m, 1H), 7.22-7.10 (m, 3H),hydroxy-4-propionamidobutyl)- 537 4.18 (d, J = 13.2 Hz, 1H), 4.06-3.98(m, N-((S)-1-cyclohexyl-3- 1H), 3.86 (d, J = 12.6 Hz, 1H),(methylamino)propan-2- 3.02-2.93 (m, 3H), 2.83 (dd, J = 12.6, 10.2 Hz,yl)piperidine-1-carboxamide 1H), 2.59 (s, 3H), 2.47-2.38 (m, 2H), 2.04(q, J = 7.6 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H), 1.90-0.77 (m, 22H).I-417A (3R)-3-(1-(2-(cyclopropylmethoxy)- 121 536 0.82 (m, 1H), 1.10 (s,9H), 1.86 (m, 1H), 3-fluorophenyl)-1-hydroxy-5- 2.58 (m, 1H), 2.70 (s,3H), 2.84 (m, 1H), methoxypentyl)-N-((S)-4,4-dimethyl- 2.96 (m, 2H),3.26 (s, 3H), 4.05 (m, 1H), 1-(methylamino)pentan-2- 4.24 (m, 2H), 4.89(m, 1H), 6.96 (m, yl)piperidine-1-carboxamide 2H), 7.27 (m, 1H) I-418A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.36 536, 7.36-7.35 (m, 1H),7.26-7.15 (m, 3H), hydroxy-4-(3-methylureido)butyl)- 538 4.21 (d, J =13.5 Hz, 1H), 4.10-4.03 (m, N-((S)-1-cyclohexyl-3- 1H), 3.92 (d, J =13.8 Hz, 1H), (methylamino)propan-2- 3.01-2.97 (m, 3H), 2.86 (dd, J =12.6, 10.2 Hz, yl)piperidine-1-carboxamide 1H), 2.64 (s, 3H), 2.59 (s,3H), 2.52-2.44 (m, 2H), 1.94-0.79 (m, 22H). I-421A(3R)-N-((2S,3S)-3-amino-1- 119 508 1.29 (m, 3H), 2.54 (m, 2H), 3.29 (s,3H), cyclohexylbutan-2-yl)-3-((S)-1-(3- 3.54 (m, 1H), 3.14 (m, 3H), 3.82(m, chlorophenyl)-1-hydroxy-5- 1H), 3.96 (m, 1H), 4.30 (m, 1H),methoxypentyl)piperidine-1- 7.28 (m, 3H), 7.44 (m, 1H) carboxamideI-423A (3R)-3-((S)-4-acetamido-1-(3- 121 539 1.88 (s, 3H), 2.16 (m, 1H),2.64 (m, 1H), chloro-2-fluorophenyl)-1- 2.71 (s, 3H), 2.88 (m, 2H), 4.02(d, 1H), hydroxybutyl)-N-((S)-1-cyclohexyl- 4.15 (m, 1H), 4.32 (d, 1H),7.16 (m, 3-(methylamino)propan-2- 1H), 7.48 (m, 1H), 7.54 (m, 1H)yl)piperidine-1-carboxamide I-424A (3R)-3-((S)-4-acetamido-1-(3- 121 5390.89 (m, 1H), 1.03 (m, 1H), 1.89 (s, 3H), chloro-5-fluorophenyl)-1- 1.96(m, 1H), 2.56 (m, 2H), 2.71 (s, 3H), hydroxybutyl)-N-((S)-1-cyclohexyl-2.92 (m, 1H), 3.05 (m, 3H), 3.96 (d, 3-(methylamino)propan-2- 1H), 4.12(m, 1H), 4.29 (d, 1H), yl)piperidine-1-carboxamide 7.07 (m, 2H), 7.24(m, 1H) I-425A (3R)-3-((S)-4-acetamido-1-(2- 121 539 0.90 (m, 2H), 1.02(m, 2H), 1.87 (s, 3H), chloro-3-fluorophenyl)-1- 1.95 (m, 1H), 2.46 (m,1H), 2.64 (m, hydroxybutyl)-N-((S)-1-cyclohexyl- 2H), 2.71 (s, 3H), 2.92(m, 2H), 3.08 (m, 3-(methylamino)propan-2- 3H), 4.00 (d, 1H), 4.15 (m,1H), 4.32 (d, yl)piperidine-1-carboxamide 1H), 7.15 (m, 1H), 7.30 (m,1H), 7.60 (m, 1H) I-426A (3R)-3-((S)-1-(3-chloro-2- 33 1.72 540,7.35-7.29 (m, 2H), 7.06 (t, J = 8.0 Hz,fluorophenyl)-1,5-dimethoxypentyl)- 542 1H), 4.22 (d, J = 12.9 Hz, 1H),N-((S)-1-cyclohexyl-3- 4.04-3.97 (m, 1H), 3.88 (d, J = 12.9 Hz, 1H),(methylamino)propan-2- 3.31-3.27 (m, 2H), 3.20 (s, 3H), 3.15 (s,yl)piperidine-1-carboxamide 3H), 2.94 (dd, J = 12.7, 3.4 Hz, 1H), 2.83(dd, J = 12.6, 10 Hz, 1H), 2.59 (s, 3H), 2.36-0.76 (m, 26H). I-427A(3R)-N-((2R,3S)-3-hydroxy-4- 117 1.42 543 0.76 (3H, d), 0.88 (3H, d),1.76 (1H, m), methyl-1-(methylamino)pentan-2- 2.84 (3H, s), 3.26 (3H,s), 3.95 (2H, m), yl)-3-((S)-1-hydroxy-5-methoxy-1- 4.28 (1H, d), 6.72(1H, m), 6.93 (2H, m), (2-phenoxyphenyl)pentyl)piperidine- 7.14 (3H, m),7.35 (2H, m), 7.64 (1H, 1-carboxamide m). I-428A(3R)-3-((S)-1-(3-chloro-2- 117 1.45 542 0.82 (m), 1.04-2.04 (m), 2.18(m), fluorophenyl)-1-hydroxy-5- 2.64 (m), 2.72 (s), 2.78 (m), 3.04 (dd),methoxypentyl)-N-((1S,2R)-1- 3.24 (s), 3.30 (t), 3.42 (m), 3.82, 3.98(d), cyclohexyl-1-hydroxy-3- 4.12 (m), 4.38, 4.50 (d), 7.16 (dd),(methylamino)propan-2- 7.38 (dd), 7.56 (dd) yl)piperidine-1-carboxamideI-428A (3R)-3-((S)-1-(3-chloro-2- 121 542 0.84 (m, 1H), 1.88 (m, 2H),2.16 (m, fluorophenyl)-1-hydroxy-5- 1H), 2.64 (m, 1H), 2.71 (s, 3H),2.38 (m, methoxypentyl)-N-((1S,2R)-1- 1H), 3.04 (m, 1H), 3.26 (s, 3H),3.44 (m, cyclohexyl-1-hydroxy-3- 1H), 3.96 (d, 1H), 4.12 (m, 1H), 4.36(d, (methylamino)propan-2- 1H), 7.15 (m, 1H), 7.38 (m, 1H),yl)piperidine-1-carboxamide 7.54 (m, 1H) I-429A(3R)-3-((S)-1-(3-chloro-2- 120 542 2.17 (m, 1H), 2.65 (m, 1H), 2.70 (s,3H), fluorophenyl)-1-hydroxy-5- 2.78 (m, 1H), 3.00 (m, 2H), 3.26 (s,3H), methoxypentyl)-N-((S)-1-(cis-4- 3.94 (m, 1H), 3.96 (d, 1H), 4.12(m, hydroxycyclohexyl)-3- 1H), 4.36 (d, 1H), 7.15 (m, 1H),(methylamino)propan-2- 7.37 (m, 1H), 7.54 (m, 1H)yl)piperidine-1-carboxamide I-429B (3R)-3-((S)-1-(3-chloro-2- 121 5420.84 (m, 1H), 1.96 (m, 2H), 2.62 (m, fluorophenyl)-1-hydroxy-5- 1H),2.70 (s, 3H), 2.35 (m, 2H), 3.06 (m, methoxypentyl)-N-((S)-1-(trans-4-1H), 3.96 (m, 1H), 4.12 (m, 1H), hydroxycyclohexyl)-3- 4.34 (m, 1H),7.15 (m, 1H), 7.37 (m, 1H), (methylamino)propan-2- 7.54 (m, 1H)yl)piperidine-1-carboxamide I-430A (3R)-3-((S)-1-(2-chloro-3- 121 5420.76 (m, 1H), 2.48 (m, 1H), 2.73 (s, 3H), fluorophenyl)-1-hydroxy-5-2.92 (m, 1H), 3.05 (m, 1H), 3.25 (s, 3H), methoxypentyl)-N-((1S,2R)-1-3.46 (m, 1H), 3.94 (d, 1H), 4.12 (m, cyclohexyl-1-hydroxy-3- 1H), 4.34(d, 1H), 7.16 (m, 1H), (methylamino)propan-2- 7.34 (m, 1H), 7.62 (m, 1H)yl)piperidine-1-carboxamide I-431A 3-(1-acetamido-1-(3-chlorophenyl)-133 1.47 542, 7.80-7.14 (m, 8H), 4.42 (m, 1H), 3.27 (t,5-methoxypentyl)-N-((S)-1- 544 J = 6.2 Hz, 2H), 3.20 (s, 3H),cyclohexyl-3-(methylamino)propan- 3.11-2.93 (m), 2.63 (s, 3H), 2.58-2.41(m), 1.95 (s, 2-yl)benzamide 3H), 1.79-0.84 (m). I-432A(3R)-3-((S)-1-(3-chloro-2- 119 544 0.82 (m, 1H), 1.80 (m, 1H), 2.71 (s,3H), fluorophenyl)-1-hydroxy-5- 2.80 (m, 1H), 2.92 (m, 1H), 3.05 (m,methoxypentyl)-N-((S)-1-(trans-4- 1H), 3.25 (s, 3H), 3.96 (d, 1H), 4.11(m, fluorocyclohexyl)-3- 1H), 4.34 (m, 1H), 7.12 (m, 1H),(methylamino)propan-2- 7.39 (m, 1H), 7.55 (m, 1H)yl)piperidine-1-carboxamide I-432B (3R)-3-((S)-1-(3-chloro-2- 119 5440.84 (m, 1H), 2.15 (m, 1H), 2.71 (s, 3H), fluorophenyl)-1-hydroxy-5-2.82 (m, 1H), 2.94 (m, 1H), 3.06 (m, methoxypentyl)-N-((S)-1-(cis-4-1H), 3.25 (s, 3H), 3.94 (d, 1H), 4.16 (m, fluorocyclohexyl)-3- 1H), 4.36(d, 1H), 7.13 (m, 1H), (methylamino)propan-2- 7.36 (m, 1H), 7.53 (m, 1H)yl)piperidine-1-carboxamide I-433A (3R)-3-((S)-1-(3-chloro-2,4- 121 5440.84 (m, 1H), 2.70 (s, 3H), 3.06 (m, 1H), difluorophenyl)-1-hydroxy-5-3.27 (s, 3H), 3.96 (d, 1H), 4.13 (m, 1H),methoxypentyl)-N-((S)-1-cyclohexyl- 4.30 (d, 1H), 7.12 (m, 1H), 7.56 (m,1H) 3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-433B(3R)-3-((R)-1-(3-chloro-2,4- 121 544 0.86 (m, 1H), 2.17 (m, 1H), 2.70(s, 3H), difluorophenyl)-1-hydroxy-5- 2.91 (m, 1H), 3.04 (m, 1H), 3.25(s, 3H), methoxypentyl)-N-((S)-1-cyclohexyl- 3.92 (m, 1H), 4.14 (m, 1H),4.42 (m, 3-(methylamino)propan-2- 1H), 7.10 (m, 1H), 7.52 (m, 1H)yl)piperidine-1-carboxamide I-434A (3R)-3-((S)-1-(3-chloro-2- 121 5440.84 (m, 1H), 2.18 (m, 1H), 2.70 (s, 3H), fluorophenyl)-1-hydroxy-5-2.96 (m, 1H), 3.14 (m, 1H), 3.25 (s, 3H), methoxypentyl)-N-((S)-1-(1-3.84 (m, 1H), 4.38 (m, 2H), 7.15 (m, fluorocyclohexyl)-3- 1H), 7.37 (m,1H), 7.53 (m, 1H) (methylamino)propan-2- yl)piperidine-1-carboxamideI-435A (3R)-3-((S)-1-(2-chloro-3- 119 544 2.06 (m, 2H), 2.46 (m, 1H),2.71 (s, 3H), fluorophenyl)-1-hydroxy-5- 2.94 (m, 2H), 3.06 (m, 1H),3.26 (s, 3H), methoxypentyl)-N-((S)-1-(trans-4- 4.04 (m, 2H), 4.42 (m,2H), 7.15 (m, fluorocyclohexyl)-3- 1H), 7.32 (m, 1H), 7.60 (m, 1H)(methylamino)propan-2- yl)piperidine-1-carboxamide I-435B(3R)-3-((R)-1-(2-chloro-3- 119 544 2.07 (m, 2H), 2.46 (m, 1H), 2.71 (s,3H), fluorophenyl)-1-hydroxy-5- 2.92 (m, 2H), 3.07 (m, 1H), 3.26 (s,3H), methoxypentyl)-N-((S)-1-(trans-4- 3.96 (d, 1H), 4.12 (m, 1H), 4.34(d, 1H), fluorocyclohexyl)-3- 7.16 (m, 1H), 7.30 (m, 1H), 7.60 (m,(methylamino)propan-2- 1H) yl)piperidine-1-carboxamide I-436A(3R)-N-((S)-1-(cis-4- 119 546 1.08 (m, 1H), 2.70 (s, 3H), 3.06 (m, 1H),fluorocyclohexyl)-3- 3.22 (s, 3H), 4.14 (m, 3H), 6.94 (m, 1H),(methylamino)propan-2-yl)-3-((S)-1- 7.23 (m, 1H)hydroxy-5-methoxy-1-(2,3,5- trifluorophenyl)pentyl)piperidine-1-carboxamide I-437A (3R)-2-((R)-1-(3-chloro-2- 33 1.38 546 7.53 (t, 1H),7.36 (t, 1H), 7.12 (t, 1H), fluorophenyl)-1-hydroxy-5- 4.48 (m, 1H),4.36 (m, 1H), 3.43 (t, 2H), methoxypentyl)-N-((S)-1-(trans-4- 3.24 (s,3H), 2.70 (s, 3H), 0.85 (m, 1H). fluorocyclohexyl)-3-(methylamino)propan-2- yl)morpholine-4-carboxamide I-438A(3R)-3-((S)-1-(3-chlorophenyl)-4- 33 1.41 547, 7.35-7.34 (m, 1H),7.24-7.12 (m, 3H), (cyclopropanecarboxamido)-1- 549 4.19 (d, J = 13.2Hz, 1H), 4.08-4.01 (m, hydroxybutyl)-N-((S)-1-cyclohexyl- 1H), 3.88 (d,J = 13.2 Hz, 1H), 3.03 (t, J = 7.0 Hz, 3-(methylamino)propan-2- 2H),2.97 (dd, J = 12.6, 3.5 Hz, yl)piperidine-1-carboxamide 1H), 2.85 (dd, J= 12.5, 10.1 Hz, 1H), 2.61 (s, 3H), 2.49-2.40 (m, 2H), 1.92-0.59 (m,27H). I-439A (3R)-3-((S)-4-butyramido-1-(3- 33 1.43 550, 7.32-7.31 (m,1H), 7.22-7.10 (m, 3H), chlorophenyl)-1-hydroxybutyl)- 552 4.18 (d, J =12.9 Hz, 1H), 4.06-3.99 (m, N-((S)-1-cyclohexyl-3- 1H), 3.85 (d, J =13.2 Hz, 1H), (methylamino)propan-2- 3.02-2.93 (m, 3H), 2.83 (dd, J =12.6, yl)piperidine-1-carboxamide 10.2 Hz, 1H), 2.59 (s, 3H), 2.46-2.37(m, 2H), 2.00 (q, J = 7.3 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H), 1.90-0.76(m, 24H). I-440A (3R)-3-((S)-1-(3-chlorophenyl)-4- 33 1.38 550, 7.35 (m,1H), 7.26-7.15 (m, 3H), (3,3-dimethylureido)-1- 552 4.20 (d, J = 13.5Hz, 1H), 4.10-4.04 (m, 1H), hydroxybutyl)-N-((S)-1-cyclohexyl- 3.94 (d,J = 12.9 Hz, 1H), 3.06-2.98 (m, 3-(methylamino)propan-2- 3H), 2.86 (dd,J = 12.5, 10.4 Hz, 1H), yl)piperidine-1-carboxamide 2.78 (s, 6H), 2.64(s, 3H), 2.54-2.44 (m, 2H), 1.93-0.79 (m, 22H). I-442A(3R)-3-((S)-1-(3-bromophenyl)-1- 33 1.56 552 0.84-1.12 (m), 1.20-2.04(m), 2.58 (m), hydroxy-5-methoxypentyl)-N-((S)-1- 2.72 (s), 2.94 (dd),3.06 (d), 3.26 (s), cyclohexyl-3-(methylamino)propan- 3.28 (t), 3.98(d), 4.14 (m), 4.28 (d), 2-yl)piperidine-1-carboxamide 7.24 (m), 7.36(d), 7.40 (d), 7.60 (s) I-447A (3R)-3-((S)-1-(3-chloro-2- 117 1.52 5562.72 (3H, s), 3.25 (3H, s) 4.07 (1H, m), fluorophenyl)-1-hydroxy-5- 3.99(1H, d), 4.13 (1H, d), 7.14 (1H, m), methoxypentyl)-N-((1R,2R)-1- 7.37(1H, m), 7.52 (1H, m). cycloheptyl-1-hydroxy-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-449A (3R)-3-((S)-1-(3-chlorophenyl)-1- 331.38 558, 7.34 (m, 1H), 7.23-7.11 (m, 3H), hydroxy-4- 560 4.20 (d, J =12.9 Hz, 1H), 4.06-3.99 (m, 1H), (methylsulfonamido)butyl)-N-((S)-1-3.86 (d, J = 12.6 Hz, 1H), 2.97-2.81 (m,cyclohexyl-3-(methylamino)propan- 4H), 2.76 (s, 3H), 2.59 (s, 3H),2-yl)piperidine-1-carboxamide 2.48-2.42 (m, 2H), 1.96-0.75 (m, 22H).I-450A (3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.33 559, 7.33-7.32 (m, 1H),7.22-7.09 (m, 3H), hydroxy-4-(sulfamoylamino)butyl)- 561 4.19 (d, J =13.2 Hz, 1H), 4.05-3.98 (m, N-((S)-1-cyclohexyl-3- 1H), 3.84 (d, J =13.2 Hz, 1H), (methylamino)propan-2- 2.96-2.81 (m, 4H), 2.59 (s, 3H),yl)piperidine-1-carboxamide 2.48-2.40 (m, 2H), 1.95-0.76 (m, 22H).I-451A (3R)-3-((S)-4-acetamido-1-(2,3- 33 1.26 559 7.31-7.26 (m, 1H),7.12-7.02 (m, 2H), difluorophenyl)-1-hydroxybutyl)- 4.25 (d, J = 13.8Hz, 1H), 4.10-4.03 (m, N-((S)-1-(4,4-difluorocyclohexyl)-3- 1H), 3.90(d, J = 12.3 Hz, 1H), (methylamino)propan-2- 3.03-2.98 (m, 3H), 2.87(dd, J = 12.6, 10.2 Hz, yl)piperidine-1-carboxamide 1H), 2.71 (t, J =12.2 Hz, 1H), 2.63 (s, 3H), 2.59-2.53 (m, 1H), 1.80 (s, 3H), 2.08-0.89(m, 20H). I-452A (3R)-3-((S)-1-(3-fluoro-2- 117 1.41 561 0.76 (3H, d),0.88 (3H, d), 1.80 (1H, m), phenoxyphenyl)-1-hydroxy-5- 2.70 (3H, s),3.30 (3H, s), 3.90 (1H, d), methoxypentyl)-N-((2R,3S)-3- 3.95 (1H, m),4.30 (1H, d), 6.80 (2H, hydroxy-4-methyl-1- m), 7.03 (1H, m), 7.13 (1H,m), (methylamino)pentan-2- 7.25 (3H, m), 7.50 (1H, m).yl)piperidine-1-carboxamide I-454A I-455A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.43 565, 7.32-7.31 (m, 1H),7.21-7.10 (m, 3H), hydroxy-4-((R)-2- 567 4.18 (d, J = 12.9 Hz, 1H),4.05-3.98 (m, methoxypropanamido)butyl)-N-((S)- 1H), 3.84 (d, J = 12.9Hz, 1H), 3.56 (q, 1-cyclohexyl-3- J = 6.7 Hz, 1H), 3.21 (s, 3H),(methylamino)propan-2- 3.11-2.97 (m, 2H), 2.94 (dd, J = 12.6, 3.2 Hz,1H), yl)piperidine-1-carboxamide 2.82 (dd, J = 12.5, 10.4 Hz, 1H), 2.58(s, 3H), 2.46-2.35 (m, 2H), 1.16 (d, J = 6.7 Hz, 3H), 1.89-0.73 (m,22H). I-455B (3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.41 565, 7.31-7.30(m, 1H), 7.21-7.09 (m, 3H), hydroxy-4-((S)-2- 567 4.17 (d, J = 12.9 Hz,1H), 4.05-3.97 (m, methoxypropanamido)butyl)-N-((S)- 1H), 3.85 (d, J =12.3 Hz, 1H), 3.55 (q, 1-cyclohexyl-3- J = 6.7 Hz, 1H), 3.20 (s, 3H),(methylamino)propan-2- 3.06-3.00 (m, 2H), 2.94 (dd, J = 12.7, 3.4 Hz,1H), yl)piperidine-1-carboxamide 2.82 (dd, J = 12.5, 10.4 Hz, 1H), 2.58(s, 3H), 2.45-2.34 (m, 2H), 1.16 (d, J = 6.7 Hz, 3H), 1.89-0.73 (m,22H). I-456A (3R)-3-((S)-1-(3-chlorophenyl)-1- 121 510 0.98 (m, 2H),1.94 (m, 1H), 2.45 (m, hydroxy-2-(2-methoxyethoxy)ethyl)- 1H), 2.70 (s,3H), 2.42 (m, 1H), 3.06 (m, N-((S)-1-cyclohexyl-3- 1H), 3.29 (m, 3H),3.50 (m, 2H), (methylamino)propan-2- 3.62 (m, 2H), 3.72 (m, 1H), 3.83(m, 2H), yl)piperidine-1-carboxamide 4.00&4.34 (m, 1H), 4.16 (m, 2H),7.30 (m, 3H), 7.52 (m, 1H) I-457A (3R)-N-((1S,2R)-1-cyclopentyl-1- 1171.47 568 2.70 (3H, s), 3.30 (3H, s), 3.95 (2H, m),hydroxy-3-(methylamino)propan-2- 4.35 (1H, d), 6.77 (1H, d, 8.4), 6.97(2H, yl)-3-((S)-1-hydroxy-5-methoxy-1- d, 8.4), 7.15 (2H, m), 7.23 (1H,t, 6.8), (2-phenoxyphenyl)pentyl)piperidine- 7.40 (2H, t, 7.6), 7.70(1H, d, 6.4). 1-carboxamide I-458A 2-(1-acetamido-1-(3-chloro-2- 1331.45 569 7.41-7.31 (m, 2H), 7.13 (q, 1H), 3.39 (m,fluorophenyl)-5-methoxypentyl)- 2H), 3.04 (m, 1H), 2.67 (s, 3H), 1.00(m, N-((S)-1-cyclohexyl-3- 1H), 0.89 (m, 1H). (methylamino)propan-2-yl)morpholine-4-carboxamide I-459A (3R)-3-((S)-1-(2-bromo-5- 33 1.59 5700.70-1.16 (m), 1.20-1.90 (m), 2.64 (m), fluorophenyl)-1-hydroxy-5- 2.70(s), 2.78 (m), 2.94 (dd), 3.06 (dd), methoxypentyl)-N-((S)-1-cyclohexyl-3.24 (s), 3.30 (t), 4.02 (d), 4.14 (m), 3-(methylamino)propan-2- 4.30(d), 6.92 (m), 7.58 (m) yl)piperidine-1-carboxamide I-463A(3R)-3-((S)-1-(3-fluoro-2-(o- 117 1.45 575 0.80 (3H, d), 0.95 (3H, d),1.70 (1H, m), tolyloxy)phenyl)-1-hydroxy-5- 2.50 (3H, 2d), 3.20 (3H, s),3.30 (3H, s), methoxypentyl)-N-((2R,3S)-3- 3.80 (1H, d), 4.00 (1H, m),4.25 (1H, d), hydroxy-4-methyl-1- 6.40 (1H, m), 6.90 (1H, m), 7.05 (1H,(methylamino)pentan-2- m), 7.15 (1H, m), 7.30 (2H, m),yl)piperidine-1-carboxamide 7.50 (1H, m). I-464A(3R)-3-((S)-1-(3-chlorophenyl)-1- 33 1.56 577575, not determinedhydroxy-4-(2,2,2- trifluoroacetamido)butyl)-N-((S)-1-cyclohexyl-3-(methylamino)propan- 2-yl)piperidine-1-carboxamide I-466A(3R)-N-((1S,2R)-1-cyclopentyl-1- 117 1.45 586 2.75 (3H, s), 3.40 (3H,s), 3.95 (1H, d), hydroxy-3-(methylamino)propan-2- (M + 1) 4.00 (1H, m),4.35 (1H, d), 6.85 (2H, d), yl)-3-((S)-1-(3-fluoro-2- 7.10 (1H, t), 7.20(1H, t), 7.35 (3H, m), phenoxyphenyl)-1-hydroxy-5- 7.60 (1H, d).methoxypentyl)piperidine-1- carboxamide I-467A(3R)-3-((S)-1-(3′-chloro-6- 119 588 1.81 (s, 1H), 2.66 (s, 3H), 3.25 (s,3H), fluorobiphenyl-2-yl)-1-hydroxy-5- 3.64 (m, 1H), 4.00 (m, 1H), 4.34(m, methoxypentyl)-N-((S)-1- 1H), 4.60 (m, 1H), 7.25 (m, 1H),cyclopentyl-3-(methylamino)propan- 7.35-7.47 (m, 5H), 7.62 (m, 1H)2-yl)piperidine-1-carboxamide I-468A(3R)-N-(1-(3,3-difluorocyclobutyl)-3- 33 1.52 592 7.49 (d), 7.27-7.19(m), 7.11 (t), (methylamino)propan-2-yl)-3-((S)-1- 6.99 (m), 6.78 (d),4.41 (d), 4.22 (d), (3-fluoro-2-phenoxyphenyl)-1- 3.95 (m), 3.85 (d),3.70 (d), 3.27 (m), hydroxy-5- 3.21 (m), 2.65 (s)methoxypentyl)piperidine-1- carboxamide I-469A(3R)-3-((S)-1-butyramido-1-(3- 133 1.55 595 8.01 (d, 1H), 7.40 (t, 1H),7.28 (t, 1H), chloro-2-fluorophenyl)-5- 7.15 (t, 1H), 4.29 (m, 1H), 4.12(m, 1H), methoxypentyl)-N-((S)-1-cyclohexyl- 3.92 (d, 1H), 3.37 (t, 2H),3.29 (s, 3H), 3-(methylamino)propan-2- 2.71 (s, 3H), 2.54 (t, 1H), 1.92(d, 1H), yl)piperidine-1-carboxamide 1.84 (d, 1H), 0.99 (t, 3H). I-470A(3S)-3-(1-(3-chloro-2-fluorophenyl)- 33 1.79 510 7.34 (t, J = 7.2 Hz,1H), 7.20 (t, J = 7.2 Hz, 5-methoxypentyl)-N-((S)-1- 1 H), 7.13 (t, J =7.2 Hz, 1 H), cyclohexyl-3-(methylamino)propan- 4.12-3.85 (m, 3 H), 3.66(brd, J = 13.2 Hz, 1 2-yl)piperidine-1-carboxamide H), 3.25 (s, 3 H),3.05 and 2.92 (m, 1 H), 3.00 (dd, J = 12.4, 3.2 Hz, 1 H), 2.83 (t, J =11.1 Hz, 2 H), 2.77-2.73 (m, 1 H), 2.65 (s, 3 H), 2.47 (t, J = 12.0 Hz,1 H), 2.13-2.09 (m, 1 H), 1.84 (m, 1 H), 1.78-1.64 (m, 8 H), 1.58-1.17(m, 9 H), 1.13-1.04 (m, 4 H), 0.99 (m, 1 H), 0.87 (m, 1 H). I-471A(R)-2-((S)-(3-chloro-2- 33 1.56 514 7.42 (t, 1H), 7.37 (t, 1H), 7.19 (t,1H), fluorophenyl)(3- 4.61 ((d, 1H), 4.11 (d, 2H), 3.80 (t, 2H),methoxypropoxy)methyl)-N-((S)-1- 3.55 (t, 1H), 3.28 (s, 3H), 3.04 (td,1H), cyclohexyl-3-(methylamino)propan- 2.69 (s, 3H), 1.48 (m, 1H), 1.01(m, 1H), 2-yl)morpholine-4-carboxamide 0.89 (m, 1H). I-472A(3R)-N-((S)-2-amino-5-methoxy- 127 1.45 516 0.82 (m), 0.98 (s), 1.00(s), 4,4-dimethylpentyl)-3-((S)-1-(3- 1.18-1.64 (m), 1.96 (m), 2.20 (m),2.68 (m), chloro-2-fluorophenyl)-1-hydroxy-5- 3.16 (d), 3.24 (sd), 3.30(m), 3.38 (s), 3.86 (d), methoxypentyl)piperidine-1- 4.42 (d), 7.14(dd), 7.38 (dd), 7.54 (dd). carboxamide I-473A(3R)-N-((S)-1-amino-5-methoxy- 33 1.44 516 0.82 (m), 0.98 (s), 1.12-1.64(m), 4,4-dimethylpentan-2-yl)-3-((S)-1- 1.98 (m), 2.18 (m), 2.64 (m),2.78 (dd), (3-chloro-2-fluorophenyl)-1- 2.84 (dd), 2.98 (m), 3.10 (s),3.24 (s), hydroxy-5- 3.30 (m), 3.34 (s), 3.94 (d), 4.12 (m), 4.38 (d),methoxypentyl)piperidine-1- 7.14 (dd), 7.38 (dd), 7.54 (dd). carboxamideI-474A (3R)-3-((S)-1-(3-chlorophenyl)-1- 119 522 1.12 (d, 3H), 2.54 (m,2H), 2.72 (s, 3H), hydroxy-5-methoxypentyl)- 3.14 (m, 1H), 3.26 (s, 3H),3.93 (m, 2H), N-((2S,3R)-1-cyclohexyl-3- 4.17 (m, 1H), 4.32 (m, 1H),7.26 (m, 3H), (methylamino)butan-2-yl)piperidine- 7.43 (m, 1H)1-carboxamide I-475A (3R)-3-((S)-1-(3-chloro-2- 127 1.56 526 7.52 (t,1H), 7.36 (t, 1H), 7.13 (t, 1H), fluorophenyl)-1-hydroxy-5- 4.40 (d,1H), 3.89 (d, 1H), 3.53 (d, 1H), methoxypentyl)-N-((S)-3- 3.24 (s, 3H),2.73 (s, 3H), 2.18 (tt, 1H), cyclohexyl-2- 1.00 (m, 1H), 0.83 (m, 1H).(methylamino)propyl)piperidine-1- carboxamide I-476A(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 526 0.98 (m, 1H), 2.38 (m, 1H),2.71 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.96 (m, 1H), 3.13 (m,1H), 3.23 (s, 3H), (1-fluorocyclohexyl)-3- 3.81&3.98 (m, 1H), 4.35 (m,2H), (methylamino)propan-2- 7.25 (m, 3H), 7.42 (m, 1H)yl)piperidine-1-carboxamide I-476B (3R)-3-((S)-1-(3-chlorophenyl)-1- 1211.52 526 7.42 (s), 7.27 (m), 7.22 (m), 4.38 (d),hydroxy-5-methoxypentyl)-N-((S)-1- 4.20 (br m), 3.83 (d), 3.26 (s), 2.72(m), (1-fluorocyclohexyl)-3- 2.58 (m), 2.46 (s), 2.39 (t).(methylamino)propan-2- yl)piperidine-1-carboxamide I-476C(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 1.51 526 7.42 (s), 7.28 (m), 7.22(m), 4.28 (d), hydroxy-5-methoxypentyl)-N-((R)-1- 4.19 (br m), 3.95 (d),3.27 (s), 2.65 (m), (1-fluorocyclohexyl)-3- 2.57 (q), 2.42 (s).(methylamino)propan-2- yl)piperidine-1-carboxamide I-477A(3R)-N-((2R,3S)-3-amino-4- 127 526 0.80 (m, 1H), 1.30 (s, 3H), 2.18 (m,2H), cyclohexylbutan-2-yl)-3-((S)-1-(3- 2.68 (m, 2H), 3.25 (s, 3H), 3.88(m, 1H), chloro-2-fluorophenyl)-1-hydroxy-5- 4.04 (m, 1H), 4.44 (m, 1H),7.15 (m, 1H), methoxypentyl)piperidine-1- 7.36 (m, 1H), 7.54 (m, 1H)carboxamide I-477B (3R)-N-((2S,3S)-3-amino-4- 127 526 0.80 (m, 1H), 1.30(s, 3H), 2.18 (m, 2H), cyclohexylbutan-2-yl)-3-((S)-1-(3- 2.68 (m, 2H),3.25 (s, 3H), 3.88 (m, 1H), chloro-2-fluorophenyl)-1-hydroxy-5- 4.04 (m,1H), 4.44 (m, 1H), 7.15 (m, 1H), methoxypentyl)piperidine-1- 7.36 (m,1H), 7.54 (m, 2H) carboxamide I-478A(3R)-3-(1-(3-chloro-2-fluorophenyl)- 149 1.71 528, 7.41-7.27 (m, 2H),7.16-7.06 (m, 1H), 1-fluoro-5-methoxypentyl)-N-((S)-1- 530 4.34-3.63 (m,3H), 3.23-3.18 (m, 2H), cyclohexyl-3-(methylamino)propan- 3.15 (s, 3H),3.00-2.48 (m, 4H), 2.57 (s, 2-yl)piperidine-1-carboxamide 3H), 2.17-0.72(m, 24H). I-479A (3R)-3-((S)-1-(benzo[b]thiophen-7- 33 1.32 532yl)-1-hydroxy-5-methoxypentyl)-N- (1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine-1- carboxamide I-480A(3R)-3-((S)-1-(2,3- 151 532 2.72 (m, 3H), 2.90 (m, 3H), 3.28 (s, 3H),dihydrobenzofuran-7-yl)-1-hydroxy- 4.05 (m, 2H), 4.30 (m, 2H), 7.22 (m,1H), 5-methoxypentyl)-N-((S)-1-((1r,4S)- 7.50 (m, 1H), 7.74 (m, 1H)4-fluorocyclohexyl)-3- (methylamino)propan-2-yl)piperidine-1-carboxamide I-481A (3R)-3-((S)-1-(3-chlorophenyl)-1- 331.76 536, 7.32-7.17 (m, 4H), 4.24 (d, J = 13.2 Hz,ethoxy-5-methoxypentyl)-N-((S)-1- 538 1H), 4.06-3.99 (m, 1H), 3.88 (d, J= 12.6 Hz, cyclohexyl-3-(methylamino)propan- 1H), 3.40-3.31 (m, 3H),3.23 (s, 3H), 2-yl)piperidine-1-carboxamide 3.19-3.11 (m, 1H), 2.97 (dd,J = 12.7, 3.4 Hz, 1H), 2.85 (dd, J = 12.6, 10.0 Hz, 1H), 2.62 (s, 3H),2.30-0.75 (m, 26H), 1.19 (t, J = 7.0 Hz, 3H). I-482A(3R)-3-((S)-1-(3-chlorophenyl)-1- 119 538 1.02 (m, 2H), 1.19 (s, 3H),1.96 (m, 2H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.52 (m, 2H), 2.71 (s,3H), 2.94 (m, 1H), ((1r,4S)-4-hydroxy-4- 3.07 (m, 1H), 3.27 (s, 3H),3.96 (m, 1H), methylcyclohexyl)-3- 4.10 (m, 1H), 4.29 (m, 1H), 7.27 (m,3H), (methylamino)propan-2- 7.44 (m, 1H) yl)piperidine-1-carboxamideI-483A (R)-3-((S)-1-(2,3-difluorophenyl)-1- 119 540 0.89 (m, 1H), 1.19(s, 3H), 1.98 (m, 2H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.15 (m, 1H),2.70 (s, 3H), 2.94 (m, 1H), ((1r,4S)-4-hydroxy-4- 3.06 (m, 1H), 3.28 (s,3H), 3.96 (m, 1H), methylcyclohexyl)-3- 4.12 (m, 1H), 4.34 (m, 1H), 7.13(m, 2H), (methylamino)propan-2- 7.37 (m, 1H) yl)piperidine-1-carboxamideI-484A^(b) (3R)-3-((S)-1-(2,3-difluorophenyl)-1- 121 540 1.00 (m, 3H),2.30 (m, 1H), 2.75 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.86 (m,1H), 3.10 (m, 1H), 3.27 (s, 3H), ((1r,4S)-4-methoxycyclohexyl)-3- 3.33(s, 3H), 3.75 (m, 1H), 4.20 (m, 2H), (methylamino)propan-2- 6.08 (m,1H), 7.05 (m, 2H), 7.32 (m, 1H), yl)piperidine-1-carboxamide 8.92 (brs,1H), 10.00 (brs, 1H) I-484B^(b) (3R)-3-((R)-1-(2,3-difluorophenyl)- 121540 1.00 (m, 3H), 2.32 (m, 1H), 2.76 (s, 3H),1-hydroxy-5-methoxypentyl)-N-((S)- 2.92 (m, 1H), 3.08 (m, 1H), 3.27 (s,3H), 1-((1r,4S)-4-methoxycyclohexyl)-3- 3.29 (s, 3H), 3.75 (m, 1H), 4.20(m, 2H), (methylamino)propan-2- 6.05 (m, 1H), 7.05 (m, 2H), 7.34 (m,1H), yl)piperidine-1-carboxamide 8.90 (brs, 1H), 10.00 (brs, 1H) I-485A(3R)-3-((S)-1-(3-chloro-2- 119 540 0.95 (m, 4H), 1.23 (d, 3H), 2.00 (m,2H), fluorophenyl)-1-hydroxy-5- 2.18 (m, 1H), 2.73 (s, 3H), 3.15 (m,1H), methoxypentyl)-N-((2S,3R)-1- 3.25 (s, 3H), 4.00 (m, 1H), 4.18 (m,1H), cyclohexyl-3-(methylamino)butan-2- 4.39 (m, 1H), 7.14 (m, 1H), 7.37(m, 1H), yl)piperidine-1-carboxamide 7.53 (m, 1H) I-485B(3R)-3-((R)-1-(3-chloro-2- 119 540 0.95 (m, 4H), 1.28 (m, 3H), 1.99 (m,2H), fluorophenyl)-1-hydroxy-5- 2.20 (m, 1H), 2.74 (s, 3H), 3.25 (s,3H), methoxypentyl)-N-((2S,3R)-1- 3.64 (m, 1H), 3.90 (m, 1H), 4.05 (m,1H), cyclohexyl-3-(methylamino)butan-2- 4.43 (m, 1H), 7.15 (m, 1H), 7.37(m, 1H), yl)piperidine-1-carboxamide 7.53 (m, 1H) I-488A(3R)-N-((2S,3S)-3-amino-4- 150 1.48 542 0.70-1.02 (m), 1.06-2.00 (m),2.16 (m), cyclohexyl-1-hydroxybutan-2-yl)-3- 2.64 (m), 3.20 (s), 3.24(t), 3.50 (m), ((S)-1-(3-chloro-2-fluorophenyl)-1- 3.62 (dd), 3.70 (dd),3.84 (d), 3.92 (m), hydroxy-5- 4.40 (d), 7.06 (dd), 7.34 (dd), 7.46(dd). methoxypentyl)piperidine-1- carboxamide I-489A(3R)-N-((1S,2R)-1-cyclohexyl-1- 117 544 1.77 (m, 3H), 1.93 (m, 2H), 2.21(m, 1H), hydroxy-3-(methylamino)propan-2- 2.68 (s, 3H), 2.83 (m, 1H),3.03 (m, 1H), yl)-3-((S)-1-hydroxy-5-methoxy-1- 3.27 (s, 3H), 3.40 (m,1H), 3.99 (m, 1H), (2,3,5- 4.07 (m, 1H), 4.27 (m, 1H), 6.91 (m, 1H),trifluorophenyl)pentyl)piperidine-1- 7.22 (m, 1H) carboxamide I-490A(3R)-3-((S)-1-(2-chloro-3- 121 544 0.75 (m, 1H), 1.02 (m, 1H), 2.50 (m,1H), fluorophenyl)-1-hydroxy-5- 2.71 (s, 3H), 2.95 (m, 2H), 3.15 (m,1H), methoxypentyl)-N-((S)-1-(1- 3.27 (s, 3H), 3.82&4.00 (m, 1H),fluorocyclohexyl)-3- 4.32&4.49 (m, 2H), 7.13 (m, 1H),(methylamino)propan-2- 7.30 (m, 1H), 7.62 (m, 1H)yl)piperidine-1-carboxamide I-491A (3R)-N-((S)-1-((1r,4S)-4- 119 5462.23 (m, 1H), 2.70 (s, 3H), 2.88 (m, 2H), fluorocyclohexyl)-3- 3.08 (m,1H), 3.27 (s, 3H), 4.01 (m, 1H), (methylamino)propan-2-yl)-3-((S)-1-4.08 (m, 1H), 4.26 (m, 1H), hydroxy-5-methoxy-1-(2,3,5- 4.35&4.47 (m,1H), 6.92 (m, 1H), 7.22 (m, 1H) trifluorophenyl)pentyl)piperidine-1-carboxamide I-492A (3R)-N-((S)-2-amino-3-(4,4- 127 548 0.84 (m, 1H),2.16 (m, 2H), 2.68 (m, 2H), difluorocyclohexyl)propyl)-3-((S)-1- 3.25(s, 3H), 3.40 (m, 2H), 3.88 (m, 1H), (3-chloro-2-fluorophenyl)-1- 4.42(m, 1H), 7.15 (m, 1H), 7.37 (m, 1H), hydroxy-5- 7.53 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-493A(3R)-N-((1S,2R)-3-amino-1- 117 1.55 548 7.42 (1H), 7.26 (3H), 4.30 (1H),(noradamant-3-yl)-1- 4.08 (1H), 3.73 (1H), 2.24 (1H)hydroxypropan-2-yl)-3-((S)-1-(3- chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-495A(3R)-3-((S)-1-(3-chloro-2- 121 556 0.84 (m, 1H), 1.20 (s, 3H), 1.96 (m,2H), fluorophenyl)-1-hydroxy-5- 2.17 (m, 1H), 2.73 (s, 3H), 2.95 (m,1H), methoxypentyl)-N-((S)-1-((1r,4S)-4- 3.08 (m, 1H), 3.28 (s, 3H),3.96 (m, 1H), hydroxy-4-methylcyclohexyl)-3- 4.12 (m, 1H), 4.37 (m, 1H),7.14 (m, 1H), (methylamino)propan-2- 7.37 (m, 1H), 7.54 (m, 1H)yl)piperidine-1-carboxamide I-497A (3R)-3-((S)-1-(3-chloro-2,4- 117 5600.82 (m, 1H), 1.95 (m, 2H), 2.12 (m, 1H), difluorophenyl)-1-hydroxy-5-2.74 (s, 3H), 3.04 (m, 1H), 3.26 (s, 3H), methoxypentyl)-N-((1S,2R)-1-3.42 (m, 1H), 3.96 (m, 1H), 4.10 (m, 1H), cyclohexyl-1-hydroxy-3- 4.32(m, 1H), 7.09 (m, 1H), 7.55 (m, 1H) (methylamino)propan-2-yl)piperidine-1-carboxamide I-498A (3R)-3-((S)-1-(3-chloro-2,4- 119 5622.70 (s, 3H), 2.99 (m, 4H), 3.26 (s, 3H), difluorophenyl)-1-hydroxy-5-4.02 (m, 2H), 4.43 (m, 2H), 7.11 (m, 1H),methoxypentyl)-N-((S)-1-((1r,4S)-4- 7.57 (m, 1H) fluorocyclohexyl)-3-(methylamino)propan-2- yl)piperidine-1-carboxamide I-499A(3R)-N-((1S,2R)-(3-amino-1- 117 1.55 567 7.51 (1H), 7.36 (1H), 7.13(1H), (noradamant-3-yl)-1- 4.34 (1H), 4.10 (1H), 23.73 (1H)hydroxy)propan-2-yl)-3-((S)-1-(2- fluoro-3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-502A(3R)-3-((R)-(3-chlorophenyl)(2- 33 1.52 466, 7.31-7.16 (m, 4H),4.17-4.12 (m, 1H), hydroxyethoxy)methyl)-N-((S)-1- 468 4.09-4.03 (m,1H), 4.00 (d, J = 9.1 Hz, cyclohexyl-3-(methylamino)propan- 1H), 3.82(d, J = 12.9 Hz, 1H), 2-yl)piperidine-1-carboxamide 3.60-3.57 (m, 2H),3.31-3.22 (m, 2H), 3.03-2.78 (m, 4H), 2.65 (s, 3H), 1.76-0.80 (m, 18H).I-503A (3R)-N-(2-amino-3- 127 1.47 480 7.43 ((s, 1H), 7.32-7.20 (m, 3H),4.36 (d, cyclopentylpropyl)-3-((S)-1-(3- 1H), 3.89 (d, 1H), 3.44 (t,1H), 3.27 (s, 3H), chlorophenyl)-1-hydroxy-5- 2.59 (t, 1H), 2.44 (t,1H), 1.76 (tt, 1H), methoxypentyl)piperidine-1- 1.01 (m, 1H).carboxamide I-504A (3R)-N-((2S)-2-amino-3- 127 1.35 482 7.43 (s),7.30-7.22 (m), 4.35 (d), 4.00 (br (tetrahydrofuran-2-yl)propyl)-3-((S)-m), 3.90 (m), 3.76 (m), 3.26 (m), 2.58 (t),1-(3-chlorophenyl)-1-hydroxy-5- 2.44 (t). methoxypentyl)piperidine-1-carboxamide I-505A (3R)-N-((2S)-1-amino-3- 33 1.37 482 7.43 (s),7.31-7.22 (m), 4.30 (m), 4.03 (br (tetrahydrofuran-2-yl)propan-2-yl)-m), 3.91 (m), 3.75 (m), 3.26 (m), 3-((S)-1-(3-chlorophenyl)-1- 3.12 (m),2.93 (m). hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-507A(3S)-3-((R)-1-(3-chlorophenyl)-2-(2- 121 494 0.99 (m, 1H), 1.06 (m, 2H),1.53 (m, 3H), methoxyethoxy)ethyl)-N-((S)-1- 2.71 (s, 3H), 3.08 (m, 1H),3.52 (m, 4H), cyclohexyl-3-(methylamino)propan- 3.66 (m, 2H), 4.15 (m,2H), 7.15 (m, 1H), 2-yl)piperidine-1-carboxamide 7.27 (m, 3H) I-508A(3R)-N-(2-amino-3-(tetrahydro-2H- 127 1.29 496 7.43 (s, 1H), 7.32-7.20(m, 3H), 4.36 (d, pyran-4-yl)propyl)-3-((S)-1-(3- 1H), 3.91 (m, 3H),3.26 (s, 3H), 2.58 (t, chlorophenyl)-1-hydroxy-5- 1H), 2.43 (td, 1H),1.93 (t, 1H), 1.00 (m, methoxypentyl)piperidine-1- 1H). carboxamideI-509A (3R)-N-((2S)-1-amino-3-(tetrahydro- 33 1.4 496 7.43 (s),7.28-7.23 (m), 4.30 (m), 2H-pyran-2-yl)propan-2-yl)-3-((S)-1- 4.07 (m),3.94 (m), 3.45 (m), 3.26 (m) (3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-510A (3R)-N-((S)-1-amino-3-(3-33 496 1.02 (m, 1H), 1.41 (m, 3H), 1.95 (m, 3H),methoxycyclobutyl)propan-2-yl)-3- 2.49 (m, 4H), 2.85 (m, 1H), 3.03 (m,1H), ((S)-1-(3-chlorophenyl)-1-hydroxy- 3.21 (s, 3H), 3.26 (s, 3H), 3.72(m, 1H), 5-methoxypentyl)piperidine-1- 3.90 (m, 2H), 4.30 (m, 1H), 7.26(m, 3H), carboxamide 7.44 (m, 1H) I-511A (3R)-N-((S)-2-amino-3-(trans-3-127 496 1.00 (m, 1H), 1.29 (m, 3H), 1.50 (m, 4H),methoxycyclobutyl)propyl)-3-((S)-1- 1.96 (m, 3H), 2.49 (m, 3H), 3.18 (s,3H), (3-chlorophenyl)-1-hydroxy-5- 3.26 (s, 3H), 3.77 (m, 1H), 3.88 (m,1H), methoxypentyl)piperidine-1- 4.37 (m, 1H), 7.25 (m, 3H), 7.44 (m,1H) carboxamide I-511B (3R)-N-((S)-2-amino-3-(cis-3- 127 496 1.01 (m,1H), 1.98 (m, 3H), 2.50 (m, 4H), methoxycyclobutyl)propyl)-3-((S)-1-3.16 (m, 1H), 3.27 (s, 3H), 3.29 (s, 3H), (3-chlorophenyl)-1-hydroxy-5-3.78 (m, 1H), 3.86 (m, 1H), 4.35 (m, 1H), methoxypentyl)piperidine-1-7.25 (m, 3H), 7.44 (m, 1H) carboxamide I-512A (S)-N-((S)-2-amino-3- 1271.68 496 7.32 (t, J = 7.6 Hz, 1 H), 7.20 (t, J = 7.6 Hz,cyclohexylpropyl)-3-((S)-1-(3- 1 H), 7.13 (t, J = 7.6 Hz, 1 H),chloro-2-fluorophenyl)-5- 3.73 (brd, J = 13.2 Hz, 2 H), 3.34-3.25 (m, 4methoxypentyl)piperidine-1- H), 3.24 (s, 3H), 3.14 (dd, J = 13.6, 6.8Hz, carboxamide 1 H), 2.83 (m, 2 H), 2.38 (d, J = 7.2 Hz, 1 H), 2.09(brd, J = 7.6 Hz, 1H), 1.94 (m, 1 H), 1.74-1.66 (m, 8 H), 1.54-1.48 (m,6 H), 1.37-1.15 (m, 4 H), 1.12-1.03 (m, 2 H), 0.99-0.88 (m 2 H). I-512B(S)-N-((S)-2-amino-3- 127 1.68 496 7.32 (t, J = 7.2 Hz, 1 H), 7.1--7.10(m, 2 cyclohexylpropyl)-3-((R)-1-(3- H), 4.20 (brd, J = 13.6 Hz, 1 H),chloro-2-fluorophenyl)-5- 3.73 (brd, J = 13.6 Hz, 2 H), 3.42-3.26 (m, 4methoxypentyl)piperidine-1- H), 3.25 (s, 3 H), 2.82 (t, J = 10.0 Hz, 2carboxamide H). 2.64 (t, J = 10.0 Hz 1 H), 1.90 (m, 1 H), 1.81-1.67 (m,6 H), 1.64-1.42 (m, 6 H), 1.39-1.19 (m, 3 H), 1.25-0.90 (m, 3 H). I-513A(3R)-N-((2S)-2-amino-3- 127 1.36 500 7.52 (m), 7.36 (m), 7.13 (m), 4.40(d), (tetrahydrofuran-2-yl)propyl)-3-((S)- 4.00 (br m), 3.90 (m), 3.76(m), 1-(3-chloro-2-fluorophenyl)-1- 3.44-3.35 (m), 3.24 (m), 2.68 (q)hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-514A(3R)-N-((2S)-1-amino-3- 33 1.36 500 7.52 (m), 7.36 (m), 7.13 (m), 4.34(m), (tetrahydrofuran-2-yl)propan-2-yl)- 4.03 (m), 3.91 (m), 3.76 (m),3.24 (m), 3-((S)-1-(3-chloro-2-fluorophenyl)- 3.12 (m), 2.95 (m), 2.69(m). 1-hydroxy-5- methoxypentyl)piperidine-1- carboxamide I-515A(3R)-N-((S)-2-amino-4-phenylbutyl)- 127 502 1.00 (m, 2H), 2.50 (m, 2H),2.76 (m, 2H), 3-((S)-1-(3-chlorophenyl)-1- 3.28 (s, 3H), 3.47 (m, 1H),3.89 (m, 1H), hydroxy-5- 4.36 (m, 1H), 7.16-7.48 (m, 9H)methoxypentyl)piperidine-1- carboxamide I-520A (3R)-N-((S)-2-amino-4-127 508 0.98 (m, 3H), 1.94 (m, 2H), 2.50 (m, 2H),cyclohexylbutyl)-3-((S)-1-(3- 3.17 (s, 3H), 3.88 (m, 1H), 4.35 (m, 1H),chlorophenyl)-1-hydroxy-5- 7.26 (m, 3H), 7.44 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-522A (S)-3-((R)-1-(3-chloro-2-33 1.76 510 7.33 (t, J = 7.6 Hz, 1 H), 7.13 (m, 2 H),fluorophenyl)-5-methoxypentyl)- 3.86 (brd, J = 13.2 Hz, 2 H), 3.72 (m, 1N-((S)-1-cyclohexyl-3- H), 3.25 (s, 3 H), 3.08 (m, 2 H),(methylamino)propan-2- 2.93-2.75 (m, 4 H), 2.70 (s, 3 H0, 1.93 (m, 1 H),yl)piperidine-1-carboxamide 1.85-1.65 (m, 8 H), 1.63-1.02 (m, 15 H),0.91 (m, 1 H). I-522B (S)-3-((S)-1-(3-chloro-2- 33 1.75 510 7.34 (t, J =7.6 Hz, 1 H), 7.20 (t, J = 7.6 Hz, fluorophenyl)-5-methoxypentyl)- 1 H),7.14 (t, J = 7.6 Hz, 1 H), N-((S)-1-cyclohexyl-3- 4.02 (m, 1 H), 3.79,m, 1 H), 3.67 (m, 1 H), (methylamino)propan-2- 3.24 (s, 3 H), 2.99 (ss,J = 12.8, 3.2 Hz, 1 yl)piperidine-1-carboxamide H), 2.84 (m, 2 H), 2.74(td, J = 12.8, 2.8 Hz, 1 H), 2.51 (s, 3 H), 2.48 (m, 2 H), 2.12 (m, 1H), 1.87 (m, 1 H), 1.75-1.66 (m, 8 H), 1.59-1.38 (m, 3 H), 1.32-1.20 (m,5 H), 1.13-1.08 (m, 2 H), 0.98 (m, 1 H), 0.85 (m, 1 H). I-523A(3R)-3-((S)-1-(6-fluoro-3′- 154 1.4 512 7.57 (d, J = 8.4 Hz, 1 H),7.36-7.20 (m, 3 methylbiphenyl-2-yl)-1-hydroxy-5- H), 7.04-7.02 (m, 2H), 6.92 (m, 1 H), methoxypentyl)-N-((S)-piperidin-3- 4.03 (m, 1H),3.85-3.75 (m, 2 H), yl)piperidine-1-carboxamide 3.39-3.32 (m, 3 H), 3.29(s, 3 H), 2.86 (m, 1 H), 2.71-2.56 (m, 3 H), 2.37, 2.35 (two s, 3 H,rotamer), 1.99 (m, 2 H), 1.88-1.26 (m, 13 H), 0.92 (m, 1 H). I-524A(3R)-3-((R)-(3-chloro-2- 33 1.71 512 7.43 (t, 1H), 7.33 (t, 1H), 7.21(t, 1H), fluorophenyl)(3- 4.41 (d, 1H), 4.22 (d, 1H), 4.09 (m, 1H),methoxypropoxy)methyl)-N-((S)-1- 3.89 (d, 1H), 3.27 (s, 3H), 3.05 (dd,1H), cyclohexyl-3-(methylamino)propan- 2.69 (s, 3H), 1.02 (m, 1H), 0.88(m, 1H). 2-yl)piperidine-1-carboxamide I-525A(3R)-N-(azetidin-3-ylmethyl)-3-((S)- 155 1.45 514 2.38 (s), 2.40 (s),3.18 (s), 3.26 (s), 1-(3-fluoro-2-(o-tolyloxy)phenyl)-1- 3.8-4.1 (m),6.38 (m), 6.42 (m), 6.9-7.3 (m), hydroxy-5- 7.52 (m)methoxypentyl)piperidine-1- carboxamide I-526A(3R)-N-((2S)-1-amino-3-(tetrahydro- 33 1.4 514 7.53 (m), 7.36 (m), 7.13(m), 4.35 (m), 2H-pyran-2-yl)propan-2-yl)-3-((S)-1- 4.10 (br m), 3.95(m), 3.45 (m), 3.24 (m). (3-chloro-2-fluorophenyl)-1- hydroxy-5-methoxypentyl)piperidine-1- carboxamide I-527A (3R)-N-((S)-2-amino-3-(3-127 514 0.84 (m, 1H), 1.20 (m, 1H), 2.50 (m, 2H),methoxycyclobutyl)propyl)-3-((S)-1- 2.69 (m, 3H), 3.22 (s, 3H), 3.23 (s,3H), (3-chloro-2-fluorophenyl)-1- 3.78 (m, 1H), 3.86 (m, 1H), 4.40 (m,1H), hydroxy-5- 7.11 (m, 1H), 7.38 (m, 1H), 7.52 (m, 1H)methoxypentyl)piperidine-1- carboxamide I-528A (3R)-N-((S)-1-amino-3-(3-33 514 0.83 (m, 1H), 1.20 (m, 1H), 1.45 (m, 3H),methoxycyclobutyl)propan-2-yl)-3- 1.95 (m, 3H), 2.15 (m, 1H), 2.43 (m,2H), ((S)-1-(3-chloro-2-fluorophenyl)-1- 2.64 (m, 2H), 2.80 (m, 2H),3.04 (m, 1H), hydroxy-5- 3.22 (s, 3H), 3.26 (s, 3H), 3.77 (m, 1H),methoxypentyl)piperidine-1- 3.95 (m, 2H), 4.35 (m, 1H), 7.13 (m, 1H),carboxamide 7.36 (m, 1H), 7.53 (m, 1H) I-531A(3R)-3-((R)-(3-chlorophenyl)(2- 121 521 0.98 (m, 2H), 1.12 (t, 3H), 2.21(m, 2H), propionamidoethoxy)methyl)- 2.71 (s, 3H), 3.87 (m, 1H), 4.04(m, 1H), N-((S)-1-cyclohexyl-3- 4.15 (m, 2H), 7.20 (m, 1H), 7.34 (m, 3H)(methylamino)propan-2- yl)piperidine-1-carboxamide I-533A(3R)-N-((3RS,4RS)-4- 158 1.49 522 7.36 (t, 1H), 7.19-7.10 (m, 2H), 4.40(dd, cyclohexylpiperidin-3-yl)-3-((S)-1- 1H), 3.97 (m, 2H), 3.40 (t,2H), 3.25 (s, (2,3-difluorophenyl)-1-hydroxy-5- 3H), 2.18 (q, 1H), 1.79(m, 1H), 1.12 (m, methoxypentyl)piperidine-1- 1H), 0.86 (m, 1H).carboxamide I-534A (3R)-3-((1S)-1-(3-chlorophenyl)-1,6- 1.52 522,7.37-7.36 (m, 1H), 7.26-7.14 (m, 3H), dihydroxyheptyl)-N-((S)-1- 5244.23 (d, J = 13.5 Hz, 1H), 4.10-4.02 (m,cyclohexyl-3-(methylamino)propan- 1H), 3.91 (d, J = 12.9 Hz, 1H),2-yl)piperidine-1-carboxamide 3.60-3.55 (m, 1H), 3.00 (dd, J = 12.7, 3.4Hz, 1H), 2.87 (dd, J = 12.6, 10.0 Hz, 1H), 2.64 (s, 3H), 2.52-2.44 (m,2H), 1.03 (d, J = 6.15 Hz, 3H), 1.97-0.79 (m, 26H). I-536A(3R)-N-((2S)-1-cyclohexyl-3- 121 523 0.90 (m, 1H), 1.03 (m, 1H), 1.12(t, 3H), (methylamino)propan-2-yl)-3-((R)- 1.51 (m, 1H), 2.21 (m, 2H),2.71 (s, 3H), (2,3-difluorophenyl)(2- 2.95 (m, 2H), 3.10 (m, 2H), 3.79(m, 1H), propionamidoethoxy)methyl)piperidine- 4.10 (m, 2H), 4.46 (m,1H0, 7.19 (m, 3H) 1-carboxamide I-537A (3R)-3-((S)-1-(3-chlorophenyl)-1-121 523 1.00 (m, 2H), 2.60 (m, 2H), 2.71 (s, 3H), hydroxy-2-(2- 2.95 (m,1H), 3.08 (m, 1H), 3.24 (s, 3H), methoxyacetamido)ethyl)-N-((S)-1- 4.15(m, 1H), 7.31 (m, 3H), 7.50 (m, 1H) cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-541A (3R)-N-((2S,3S)-3-amino-1- 121 5260.86 (m, 2H), 1.28 (m, 3H), 2.00 (m, 2H),cyclohexylbutan-2-yl)-3-((S)-1-(3- 2.18 (s, 2H), 2.65 (m, 1H), 2.72 (m,1H), chloro-2-fluorophenyl)-1-hydroxy-5- 3.29 (s, 3H), 3.82 (m, 1H),3.98 (m, 1H), methoxypentyl)piperidine-1- 4.36 (m, 1H), 7.13 (m, 1H),7.38 (m, 1H), carboxamide 7.53 (m, 1H) I-544A (3R)-3-((S)-1-(3-chloro-2-157 1.58 538 7.48 (td, 1H), 7.32 (tt, 1H), 7.09 (td, 1H),fluorophenyl)-1-hydroxy-5- 4.37 (dd, 1H), 3.69 (m, 1H), 3.21 (s, 3H),methoxypentyl)-N-((3RS,4RS)-4- 2.15 (m, 1H), 0.98 (m, 1H), 0.79 (m, 1H).cyclohexylpiperidin-3-yl)piperidine- 1-carboxamide I-545A(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 538 1.02 (m, 1H), 2.50 (m, 2H),2.69 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.94 (m, 1H), 3.07 (m,1H), 3.27 (s, 3H), (cis-4-methoxycyclohexyl)-3- 3.44 (m, 1H), 3.95 (m,1H), 4.10 (m, 1H), (methylamino)propan-2- 4.28 (m, 1H), 7.27 (m, 3H),7.43 (m, 1H) yl)piperidine-1-carboxamide I-545B(3R)-3-((S)-1-(3-chlorophenyl)-1- 121 538 2.09 (m, 3H), 2.52 (m, 3H),2.70 (s, 3H), hydroxy-5-methoxypentyl)-N-((S)-1- 3.10 (m, 2H), 3.27 (s,3H), 3.96 (m, 1H), (cis-4-methoxycyclohexyl)-3- 4.10 (m, 2H), 4.27 (m,1H), 7.26 (m, 3H), (methylamino)propan-2- 7.44 (m, 1H)yl)piperidine-1-carboxamide I-546A (3R)-3-((S)-4-acetamido-1-(3- 121 5390.95 (m, 4H), 1.23 (m, 3H), 1.60 (m, 3H), chloro-2-fluorophenyl)-1- 1.85(s, 3H), 1.99 (m, 3H), 2.64 (m, 1H), hydroxybutyl)-N-((2S,3R)-3-amino-2.72 (m, 1H), 3.08 (m, 2H), 4.05 (m, 2H),1-cyclohexylbutan-2-yl)piperidine-1- 4.36 (m, 1H), 7.13 (m, 1H), 7.36(m, 1H), carboxamide 7.53 (m, 1H) I-546B (3R)-3-((R)-4-acetamido-1-(3-121 539 0.95 (m, 4H), 1.22 (m, 3H), 1.88 (s, 3H),chloro-2-fluorophenyl)-1- 1.99 (m, 2H), 2.19 (m, 1H), 3.10 (m, 2H),hydroxybutyl)-N-((2S,3R)-3-amino- 7.14 (m, 1H), 7.36 (m, 1H), 7.52 (m,1H) 1-cyclohexylbutan-2-yl)piperidine-1- carboxamide I-547A(3R)-3-((R)-(3-chloro-2- 121 539 0.95 (m, 2H), 1.11 (t, 3H), 2.21 (m,2H), fluorophenyl)(2- 2.70 (s, 3H), 2.95 (m, 2H), 3.09 (m, 2H),propionamidoethoxy)methyl)- 3.79 (m, 1H), 4.10 (m, 2H), 4.45 (m, 1H),N-((2S)-1-cyclohexyl-3- 7.20 (m, 1H), 7.35 (m, 1H), 7.44 (m, 1H)(methylamino)propan-2- yl)piperidine-1-carboxamide I-548A(3R)-3-((S)-1-(2,3-difluorophenyl)-1- 121 540 0.88 (m, 2H), 1.86 (m,2H), 1.97 (m, 2H), hydroxy-5-methoxypentyl)-N-((S)-1- 2.14 (m, 2H), 2.69(s, 3H), 2.70 (m, 1H), (cis-4-methoxycyclohexyl)-3- 2.80 (m, 1H), 3.07(m, 1H), 3.26 (s, 3H), (methylamino)propan-2- 3.64 (s, 3H), 3.96 (m,1H), 4.13 (m, 1H), yl)piperidine-1-carboxamide 4.34 (m, 1H), 7.15 (m,2H), 7.36 (m, 1H) I-549A (3R)-3-((S)-1-(3-chloro-2- 158 1.55 542 7.52(t, 1H), 7.37 (t, 1H), 7.13 (t, 1H), fluorophenyl)-1-hydroxy-5- 4.43 (t,1H), 3.89 (m, 2H), 3.62 (m, 1H), methoxypentyl)-N-((3RS,4RS)-4- 3.29 (s,3H), 3.02 (t, 2H), 2.68 (m, 2H), (pentan-3-yloxy)piperidin-3- 1.97 (m,2H), 0.82 (m, 1H). yl)piperidine-1-carboxamide I-551A(3R)-N-((1S,2R)-3-amino-1-(trans- 117 1.35 546 7.53 (1H), 7.37 (1H),7.14 (1H), 4-fluorocyclohexyl)-1- 4.36 (1H), 4.10 (1H), 3.94 (1H), 3.25(3H). hydroxypropan-2-yl)-3-((S)-1-(3- 19F:−116 (1F), −171 (1F)chloro-2-fluorophenyl)-1-hydroxy-5- methoxypentyl)piperidine-1-carboxamide I-552A (3R)-3-((S)-1-(3-chlorophenyl)-1- 164 1.69 546 7.24(2H), 7.30 (1H), 7.42 (1H), 2.68 (3H) hydroxy-5-methoxypentyl)-N-((2S)-1-(3-noradamantyl)-3- (methylamino)propan-2- yl)piperidine-1-carboxamideI-553A (3R)-3-((S)-1-acetamido-5-ethoxy- 133 547 0.85 (m, 2H), 1.11 (m,1H), 1.16 (t, 3H), 1-(3-fluorophenyl)pentyl)-N-((S)-1- 1.83 (m, 1H),1.90 (m, 1H), 2.07 (s, 3H), cyclohexyl-3-(methylamino)propan- 2.18 (m,1H), 2.35 (m, 4H), 2.71 (s, 3H), 2-yl)piperidine-1-carboxamide 2.98 (m,1H), 3.05 (m, 1H), 3.45 (m, 4H), 3.88 (m, 1H), 4.10 (m, 1H), 4.19 (m,1H), 7.01 (m, 2H), 7.14 (m, 1H), 7.34 (m, 1H) I-554A(R)-3-((S)-1-(3-chloro-2- 165 1.42 547 7.53 (1H), 7.37 (1H), 7.14 (1H),fluorophenyl)-1-hydroxy-5- 4.88 (1H), 4.35 (1H), 4.07 (1H), 3.95 (1H)methoxypentyl)-N-((S)-1- 2.74 (3H) 19F:−117 (1F), −198 (2F)((1r,3R,4S)-3,4-difluorocyclopentyl)- 3-(methylamino)propan-2-yl)piperidine-1-carboxamide I-556A (3R)-3-((S)-1-(3-chloro-2- 121 5560.83 (m, 1H), 1.18 (m, 1H), 1.87 (m, 2H), fluorophenyl)-1-hydroxy-5-1.98 (m, 2H), 2.15 (m, 1H), 2.71 (s, 3H),methoxypentyl)-N-((S)-1-(cis-4- 2.72 (m, 1H), 2.94 (m, 1H), 3.07 (m,1H), methoxycyclohexyl)-3- 3.25 (s, 3H), 3.45 (m, 1H), 3.97 (m, 1H),(methylamino)propan-2- 4.13 (m, 1H), 4.33 (m, 1H), 7.13 (m, 1H),yl)piperidine-1-carboxamide 7.36 (m, 1H), 7.53 (m, 1H) I-556B(3R)-3-((S)-1-(3-chloro-2- 121 556 0.83 (m, 1H), 1.46 (m, 5H), 1.51 (m,4H), fluorophenyl)-1-hydroxy-5- 1.79 (m, 1H), 1.90 (m, 1H), 1.99 (m,2H), methoxypentyl)-N-((S)-1-(trans-4- 2.71 (s, 3H), 2.68 (m, 1H), 2.95(m, 1H), methoxycyclohexyl)-3- 3.06 (m, 1H), 3.15 (m, 1H), 3.25 (s, 3H),(methylamino)propan-2- 3.98 (m, 1H), 4.13 (m, 1H), 3.35 (m, 1H),yl)piperidine-1-carboxamide 7.13 (m, 1H), 7.36 (m, 1H), 7.53 (m, 1H)I-558A (3R)-3-((S)-1-acetamido-1-(3- 133 563 0.90 (m, 4H), 1.16 (t, 3H),1.30 (m, 7H), chlorophenyl)-5-ethoxypentyl)- 1.55 (m, 9H), 2.07 (s, 3H),2.15 (m, 1H), N-((S)-1-cyclohexyl-3- 2.71 (m, 3H), 3.00 (m, 2H), 3.45(m, 3H), (methylamino)propan-2- 3.89 (m, 1H), 4.09 (m, 1H), 4.19 (m,1H), yl)piperidine-1-carboxamide 7.26 (m, 2H), 7.32 (m, 2H) I-559A(3R)-N-((2R,3S)-2-amino-3-(3- 165 1.57 566 7.53 (t, 1H), 7.36 (t, 1H),7.13 (t, 1H), noradamantyl)-3-hydroxypropyl)-3- 4.43 (d, 1H), 3.87 (d,1H), 3.83 (s, 1H), ((S)-1-(3-chloro-2-fluorophenyl)-1- 3.63 (d, 1H),3.24 (s, 3H), 2.68 (t, 2H), hydroxy-5- 1.21 (br s, 1H), 0.83 (m, 1H).methoxypentyl)piperidine-1- carboxamide Footnotes ^(a1)H NMR spectrawere acquired in MeOH-d₄ unless otherwise noted. ^(b1)H NMR spectrumacquired in CDCl₃. ^(c)Prepared from the less polar diastereomer oftert-butyl2-((3-methoxypropoxy)(phenyl)methyl)-morpholine-4-carboxylate.^(d)Mixture of 4 diastereomers all with cis relative stereochemistryaround cyclohexane ring. ^(e)Mixture of 2 isomers of3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneseparated by prep HPLC. The stereochemical configurations of the chiralcenters on the piperidine ring and at the ether bearing carbon of theother isomer present are unknown. ^(f)Mixture of 2 isomers of3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dioneseparated by prep HPLC. The stereochemical configurations of the chiralcenters on the piperidine ring and at the ether bearing carbon areunknown. ^(g)Mixture of 2 isomers prepared from less polar fraction of2-(trimethylsilyl)ethyl(S)-2-(2-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)-3-cyclohexylpropylcarbamateseparated by preparative chiral chromatography. One of the isomerspresent has the following configuration:3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione.h Stereoisomers were separated by preparative HPLC on a chiral column

1.-30. (canceled)
 31. A compound of the following formula:

wherein R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl optionally substitutedwith 1 to 3 groups independently selected from: 1) fluorine, chlorine,bromine, cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, and heteroarylmethyl, eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy; R² is (C₂-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl,(C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy,(C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio, hydroxy(C₂-C₁₀)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy-(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy, or(C₁-C₅)-alkylthio(C₁-C₅)alkylthio; R³ is H, F, or OH; provided that whenR³ is OH or F, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or(C₁-C₅)alkylthio(C₁-C₅)alkylthio; Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is a) (C₁-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl; or b)phenyl(C₁-C₂)alkyl, or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected from fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; G is OH, NH₂, NHR⁹, or NR⁹R¹⁰; R⁹ is a) (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, oraminocarbonyl(C₁-C₆)alkyl; b) phenyl(C₁-C₂)alkyl optionally substitutedwith 1 to 3 groups independently selected from: fluorine, chlorine,cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; or c) R⁵ and R⁹ together are —CH₂—, —(CH₂)₂—,—(CH₂)₃— or —(CH₂)₄—, optionally substituted with 1 or 2 groupsindependently selected from fluorine, (C₁-C₃)alkyl and halo(C₁-C₃)alkyl,and form a 4-, 5-, 6-, or 7-membered ring with the atoms through whichthey are connected; R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; or apharmaceutically acceptable salt thereof.
 32. A compound of claim 31 ofthe following formula:

wherein R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl optionally substitutedwith 1 to 3 groups independently selected from: 1) fluorine, chlorine,bromine, cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, and heteroarylmethyl, eachoptionally substituted with 1 to 3 groups independently selected from:fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy; R² is (C₂-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₂-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl,(C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy, halo(C₂-C₁₀)alkoxy,(C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio, hydroxy(C₂-C₁₀)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy-(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkylthio(C₁-C₅)alkoxy, or(C₁-C₅)-alkylthio(C₁-C₅)alkylthio; R³ is H, F, or OH; provided that whenR³ is OH or F, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or(C₁-C₅)alkylthio(C₁-C₅)alkylthio; Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is a) (C₁-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkylthio(C₁-C₅)alkyl, halo(C₁-C₅)-alkylthio(C₁-C₅)alkyl; or b)phenyl(C₁-C₂)alkyl, or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected from fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; G is OH, NH₂, NHR⁹, or NR⁹R¹⁰; R⁹ is a) (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, oraminocarbonyl(C₁-C₆)alkyl; b) phenyl(C₁-C₂)alkyl optionally substitutedwith 1 to 3 groups independently selected from: fluorine, chlorine,cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; or c) R⁵ and R⁹ together are —CH₂—, —(CH₂)₂—,—(CH₂)₃— or —(CH₂)₄—, optionally substituted with 1 or 2 groupsindependently selected from fluorine, (C₁-C₃)alkyl and halo(C₁-C₃)alkyl,and form a 4-, 5-, 6-, or 7-membered ring with the atoms through whichthey are connected; R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; or apharmaceutically acceptable salt thereof.
 33. A compound of claim 32,wherein R¹ is a) cyclohexyl; or b) phenyl optionally substituted with 1to 3 substituents independently selected from: fluorine, chlorine,cyano, methyl, ethyl, isopropyl, trifluoromethyl, allyl,cyclopropylethynyl, phenyl, and phenoxy, wherein the phenyl and phenoxygroups are optionally substituted with 1 to 3 substituents independentlyselected from fluorine, chlorine, cyano, methyl, and trifluoromethyl; R²is butyl, hexyl, 3,3,3-trifluoropropyl, 3-(cyclopropyl)propyl,4-(cyclopropyl)butyl, 3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, or2-cyclopropylethoxy; R³ is H, F, or OH; provided that when R³ is F orOH, R² is not 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, or2-cyclopropylethoxy; Q is Q1, Q4, Q9, or Q10

R⁴ is H or methyl; R⁵ is methyl, isobutyl, 2-(trifluoromethyl)propyl,cyclopentylmethyl, cyclohexylmethyl, 4,4-difluorocyclohexylmethyl,tert-butoxymethyl, or benzyl; G is NH₂, NHR⁹, or NR⁹R¹⁰; R⁹ is methyl,ethyl, propyl, butyl, isobutyl, pentyl or isopentyl, oraminocarbonylmethyl; or R⁹ together with R⁵ is —(CH₂)₃—; R¹⁰ is methyl;or a pharmaceutically acceptable salt thereof.
 34. A compound of FormulaII

wherein Z is CH₂ or O; R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl,heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3groups independently selected from: 1) fluorine, chlorine, bromine,cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, andaminocarbonyl; R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl,fluoro(C₁-C₈)alkyl, fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy,(C₄-C₈)cycloalkylalkoxy, fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl,(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₈)alkoxy,(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, R³ is H, F, OH,(C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy; provided that when R³ is OH orF, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio, Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is a) (C₁-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated (C₄-C₁₀)cycloalkylalkyl,(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected from fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; R⁶ is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,or (C₁-C₃)alkoxy(C₁-C₃)alkyl; G is OH, NH₂, NHR⁹, or NR⁹R¹⁰; R⁹ is a)(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵ and R⁹together are —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, optionallysubstituted with 1 or 2 groups independently selected from fluorine,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,halo(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, halo(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, andhydroxylated(C₃-C₆)cycloalkyl(C₁-C₂)alkyl, and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected; R¹⁰ is(C₁-C₃)alkyl or halo(C₁-C₃)alkyl; and provided that when R² is(C₁-C₁₀)alkyl and R³ is OH, R⁶ is not (C₁-C₃)alkoxy(C₁-C₃)alkyl; or anenantiomer, diastereomer or pharmaceutically acceptable salt thereof.35. A compound of Formula IIa

wherein Z is CH₂ or O; R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl,heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3groups independently selected from: 1) fluorine, chlorine, bromine,cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-alkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl,benzyloxy, and heteroaryloxy, each optionally substituted with 1 to 3groups independently selected from: fluorine, chlorine, cyano,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, halo(C₁-C₃)alkoxy, andaminocarbonyl; R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl,fluoro(C₁-C₈)alkyl, fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy,(C₄-C₈)cycloalkylalkoxy, fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl,(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₈)alkoxy,(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, R³ is H, F, OH,(C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy; provided that when R³ is OH orF, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio, Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is a) (C₁-C₁₀)alkyl,(C₄-C₁₀)cycloalkylalkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,halo(C₄-C₁₀)cycloalkylalkyl, hydroxylated (C₄-C₁₀)cycloalkylalkyl,(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl,di(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylated(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, hydroxylateddi(C₁-C₂)alkyl(C₄-C₁₀)cycloalkylalkyl, (C₄-C₁₀)bicycloalkyl(C₁-C₂)alkyl,(C₈-C₁₂)tricycloalkyl(C₁-C₂)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, or saturated heterocyclyl(C₁-C₃)alkyl;or b) phenyl(C₁-C₂)alkyl or heteroaryl(C₁-C₂)alkyl each optionallysubstituted with 1 to 3 groups independently selected from fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; G is OH, NH₂, NHR⁹, or NR⁹R¹⁰; R⁶ is absent or is(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or (C₁-C₃)alkoxy(C₁-C₃)alkyl; R⁹ isa) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₄-C₁₀)cycloalkylalkyl,(C₁-C₅)alkoxy(C₁-C₅)alkyl, or aminocarbonyl(C₁-C₆)alkyl; or b)phenyl(C₁-C₂)alkyl optionally substituted with 1 to 3 groupsindependently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, and halo(C₁-C₃)alkoxy; or c) R⁵ and R⁹together are —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— and form a 4-, 5-, 6-, or7-membered ring with the atoms through which they are connected that isoptionally substituted with 1 or 2 groups independently selected fromfluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, andhydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl, andhydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl; R¹⁰ is(C₁-C₃)alkyl or halo(C₁-C₃)alkyl; and provided that when R² is(C₁-C₁₀)alkyl and R³ is OH, R⁶ is not (C₁-C₃)alkoxy(C₁-C₃)alkyl; orpharmaceutically acceptable salts thereof.
 36. A compound of Formula II:

wherein Z is CH₂ or O; R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl,heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3groups independently selected from: 1) fluorine, chlorine, bromine,cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)-cycloalkylalkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy,phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy andheteroaryloxy, each optionally substituted with 1 to 3 groupsindependently selected from: fluorine, chlorine, cyano, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, and halo(C₁-C₃)alkoxy, andaminocarbonyl; R² is (C₁-C₁₀)alkyl, (C₄-C₁₀)cycloalkylalkyl,halo(C₁-C₁₀)alkyl, halo(C₄-C₁₀)cycloalkylalkyl, (C₁-C₁₀)alkoxy,(C₄-C₁₀)cycloalkylalkoxy, halo(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio,halo(C₁-C₁₀)alkylthio, hydroxy(C₁-C₁₀)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl, (C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₁-C₅)alkoxy(C₁-C₅)alkyl,halo(C₃-C₆)cycloalkoxy(C(C₁-C₅)alkylthio(C₁-C₅)alkyl,halo(C₁-C₅)alkylthio(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkoxy,hydroxy(C₁-C₁₀)alkoxy, (C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy, halo(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy,hydroxy(C₁-C₁₀)-alkylthio, (C₂-C₅)alkoxy(C₁-C₅)alkylthio,(C₁-C₅)alkylthio(C₁-C₅)alkoxy, (C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)-cycloalkanecarbonylamino(C₁-C₅)alkyl,(C₃-C₄)cyclalkanecarbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylamino-carbonylamino(C₁-C₅)alkoxy, di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio, R³ is H, F, OH,(C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy; provided that when R³ is OH orF, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy,(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,(C₁-C₅)-alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio, Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is absent; R⁶ is absent or is (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, or (C₁-C₃)alkoxy(C₁-C₃)alkyl; G is OH, NH₂, NHR⁹,or NR⁹R¹⁰; R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, oraminocarbonyl(C₁-C₆)alkyl or b) phenyl(C₁-C₂)alkyl optionallysubstituted with 1 to 3 groups independently selected from: fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; or R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; andprovided that when R² is (C₁-C₁₀)alkyl and R³ is OH, R⁶ is not(C₁-C₃)alkoxy(C₁-C₃)alkyl; or an enantiomer, diastereomer orpharmaceutically acceptable salt thereof.
 37. The compound of claim 36represented by Formula IIa

wherein Z is CH₂ or O; R¹ is a) (C₃-C₇)cycloalkyl; or b) phenyl,heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3groups independently selected from: 1) fluorine, chlorine, bromine,cyano, nitro, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, (C₅-C₇)cycloalkylalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, halo(C₂-C₆)alkenyl,halo(C₃-C₆)alkynyl, halo(C₅-C₇)cycloalkyl-alkynyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy and(C₁-C₆)-alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy,heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl,benzyloxy, and heteroaryloxy, each optionally substituted with 1 to 3groups independently selected from: fluorine, chlorine, cyano,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)-alkoxy, halo(C₁-C₃)alkoxy, andaminocarbonyl; R² is (C₁-C₈)alkyl, (C₄-C₈)cycloalkylalkyl,fluoro(C₁-C₈)alkyl, fluoro(C₄-C₈)cycloalkylalkyl, (C₁-C₈)alkoxy,(C₄-C₈)cycloalkylalkoxy, fluoro(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl,C₅)alkoxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)hydroxyalkyl,(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkyl,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkyl, (C₁-C₅)alkylthio(C₁-C₅)alkyl,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₁-C₈)alkoxy,(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy, fluoro(C₁-C₅)alkoxy(C₁-C₅)alkoxy,fluoro(C₃-C₄)cycloalkoxy(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,fluoro(C₁-C₃)alkoxy(C₁-C₃)alkoxy(C₁-C₃)alkyl,aminocarbonylamino(C₁-C₈)alkyl, aminocarbonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanoylamino(C₁-C₅)alkyl, (C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,fluoro(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkyl,(C₁-C₃)alkoxy(C₁-C₅)alkanoylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkyl,(C₃-C₄)cycloalkanecarbonyllamino(C₁-C₅)alkoxy,aminosulfonylamino(C₁-C₈)alkyl, aminosulfonylamino(C₁-C₈)alkoxy,(C₁-C₅)alkanesulfonyl-amino(C₁-C₅)alkyl,(C₁-C₅)alkanesulfonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkyl,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy, R³ is H, F, OH,(C₁-C₄)alkanoylamino, or (C₁-C₃)alkoxy; provided that when R³ is OH orF, R² is not (C₂-C₁₀)alkoxy, (C₄-C₁₀)cycloalkylalkoxy,halo(C₂-C₁₀)alkoxy, (C₂-C₁₀)alkylthio, halo(C₂-C₁₀)alkylthio,(C₁-C₅)alkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkoxy,(C₃-C₆)cycloalkoxy(C₁-C₅)alkoxy, halo(C₁-C₅)alkoxy(C₁-C₅)alkoxy,halo(C₃-C₆)-cycloalkoxy(C₁-C₅)alkoxy, hydroxy(C₂-C₁₀)alkylthio,(C₂-C₅)alkoxy(C₁-C₅)alkylthio, (C₁-C₅)alkyl-thio(C₁-C₅)alkoxy, or(C₁-C₅)alkylthio(C₁-C₅)alkylthio,(C₃-C₄)cycloalkane-carbonylamino(C₁-C₅)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₅)alkylthio,alkylaminocarbonylamino(C₁-C₅)alkoxy,(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio,di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkoxy or di(C₁-C₅)alkylaminocarbonylamino(C₁-C₅)alkylthio, Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or (C₁-C₃)alkyl; R⁵ is absent; G is OH, NH₂, NHR⁹, or NR⁹R¹⁰; R⁶is absent or is (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₃)alkoxy(C₁-C₃)alkyl; R⁹ is a) (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₄-C₁₀)cycloalkylalkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, oraminocarbonyl(C₁-C₆)alkyl; or b) phenyl(C₁-C₂)alkyl optionallysubstituted with 1 to 3 groups independently selected from: fluorine,chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, andhalo(C₁-C₃)alkoxy; R¹⁰ is (C₁-C₃)alkyl or halo(C₁-C₃)alkyl; and providedthat when R² is (C₁-C₁₀)alkyl and R³ is OH, R⁶ is not(C₁-C₃)alkoxy(C₁-C₃)alkyl; or pharmaceutically acceptable salts thereof.38. A compound of Formula I

wherein R¹ is phenyl optionally substituted with chlorine; X and Y iseach independently CH₂ or a single bond; R² is substituted orunsubstituted (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,(C₁-C₁₂)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₂)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)alkylthio(C₁-C₆)alkylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, aminocarbonylamino(C₁-C₁₂)alkyl,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)-alkanoylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkyl, aminosulfonylamino(C₁-C₁₂)alkoxy,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio, wherein thesubstituted (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,(C₁-C₁₂)alkoxy, (C₁-C₁₂)alkylthio, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkoxy,(C₁-C₆)alkylthio(C₁-C₆)alkylthio,(C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, aminocarbonylamino(C₁-C₁₂)alkyl,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)-alkanoylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkyl, aminosulfonylamino(C₁-C₁₂)alkoxy,aminosulfonylamino(C₁-C₁₂)alkylthio,C₁-C₆)alkanesulfonylamino(C(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio represented by R² issubstituted by at least one of: a) one or more halogen atoms, and b) onesubstitutent selected from cyano, hydroxyl, (C₁-C₃)alkoxy,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkoxy,halo(C₃-C₆)cycloalkyl, and halo(C₃-C₆)cycloalkoxy, and wherein thethio-moiety of said unsubstituted or substituted (C₁-C₁₂)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)alkylthio(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio, is optionallyreplaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or a sulfonyl (sulfone,i.e., —S(O)₂—) moiety, and wherein the carbonyl moiety of saidunsubstituted or substituted aminocarbonylamino(C₁-C₁₂)alkyl,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)-alkanoylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkyl,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkoxy anddi(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkylthio is optionally replacedby a thiocarbonyl moiety, R³ is 1) H, halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxyl, hydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)alkylamino-carbonylamino, di(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkanesulfonylamino, (C₁-C₆)alkylaminosulfonylamino, ordi(C₁-C₆)alkylaminosulfonyl-amino, or 2) phenylamino or heteroarylaminoin which each phenylamino and heteroarylamino group is optionallysubstituted with 1 to 5 groups independently selected from: fluorine,chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkynyl,(C₃-C₆)-cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)-cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkane-sulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, amino-carbonyl,(C₁-C₆)alkylaminocarbonyl, and di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; provided that when R³ ishydroxyl, halogen or optionally substituted phenylamino orheteroarylamino, then R² is not a substituted or unsubstituted(C₁-C₁₂)alkoxy, (C₂-C₁₂)alkenyloxy, (C₁-C₁₂)alkylthio,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkoxy, (C₁-C₆)-alkylthio(C₁-C₆)alkylthio,aminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonyl-amino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy, (C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkoxy, aminosulfonylamino(C₁-C_(u))alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkoxy,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio, provided further thatwhen R³ is hydroxyl, halogen or optionally substituted phenylamino orheteroarylamino, then R² is not a unsubstituted or substituted(C₁-C₁₂)alkylthio, (C₁-C₆)alkoxy(C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkylthio, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,aminosulfonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanesulfonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio anddi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio wherein the thiomoietymoiety is replaced by a sulfinyl (sulfoxide, i.e., —S(O)—) or a sulfonyl(sulfone, i.e., —S(O)₂—) moiety, and provided further that when R³ ishydroxyl, halogen or optionally substituted phenylamino orheteroarylamino, then R² is not a unsubstituted or substitutedaminocarbonylamino(C₁-C₁₂)alkoxy, aminocarbonylamino(C₁-C₁₂)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkoxy,C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkoxy,(C₃-C₄)cycloalkanecarbonylamino(C₁-C₆)alkylthio,(C₁-C₆)alkanoylamino(C₁-C₆)alkylthio,(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio,di(C₁-C₆)alkylaminocarbonyl-amino(C₁-C₆)alkoxy ordi(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylthio, wherein the carbonylmoiety is replaced by a thiocarbonyl moiety, A is 2,4-disubstitutedmorpholine with R¹XCR²R³Y attached at the 2-position and Q attached atthe 4-position, 1,3-disubstituted piperidine with R¹XCR²R³Y attached atthe 3-position and Q attached at the 1-position,1,3-disubstituted-3-methylpiperidine with R¹XCR²R³Y attached at the3-position and Q attached at the 1-position, 1,3-disubstituted benzene,or 1,3-disubstituted cyclohexane; Q and Y are attached to carbon ornitrogen atoms in ring A in a 1,2 or 1,3 or 1,4 relationship; Q is adivalent radical selected from

R⁴ is H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl; (C₁-C₃)alkoxy(C₁-C₃)alkyl, orcyano(C₁-C₆)alkyl; L is 1) a linear (C₂-C₄)alkyl chain when G is OH,OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, NHC(═NH)NH₂, or NHC(═NH)NHR⁹, or 2) a linear(C₁-C₃)alkyl chain when G is C(═NH)NH₂ or C(═NH)NHR⁹; L is optionallysubstituted by 1-4 groups independently selected from R⁵, R⁶, R⁷, andR⁸; one or more of the carbon atoms of L may be part of a 3-, 4-, 5-,6-, or 7-membered saturated ring composed of carbon atoms, and 0-2hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms,and 0 or 1 sulfur atoms; said saturated ring being optionallysubstituted with up to four groups selected from halogen, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, halo(C₄-C₇)cycloalkylalkyl, and oxo; R⁵, R⁶, R⁷,and R⁸ is each independently selected from 1) (C₁-C₁₂)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₂-C₁₂)alkenyl,(C₅-C₈)cycloalkyl(C₁-C₃)alkenyl, (C₂-C₁₂)alkynyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkynyl, (C₄-C₁₂)bicycloalkyl(C₁-C₃)alkyl,(C₈-C₁₄)tricycloalkyl(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl, saturated heterocyclyl, and saturatedheterocyclyl(C₁-C₃)alkyl wherein (a) hydrogen atoms in these groups areoptionally substituted by 1 to 6 groups independently selected fromhalogen, cyano, hydroxyl, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, halo(C₁-C₃)alkyl,halo(C₁-C₃)alkoxy, halo(C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkoxy andwherein (b) divalent sulfur atoms are optionally oxidized to sulfoxideor sulfone; or 2) phenyl, naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl,naphthyl(C₁-C₃)alkyl, and heteroaryl(C₁-C₃)alkyl, each optionallysubstituted with 1 to 3 groups independently selected from: fluorine,chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cyclo-alkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl, (C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl, phenyl, napthyl, heteroaryl,bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, bicyclicheteroaryloxy, phenylthio, naphthylthio, heteroarylthio, bicyclicheteroarylthio, phenylsulfinyl, naphthylsulfinyl, heteroarylsulfinyl,bicyclic heteroarylsulfinyl, phenylsulfonyl, naphthylsulfonyl,heteroarylsulfonyl, bicyclic heteroarylsulfonyl, phenyl(C₁-C₃)alkyl,napthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, and bicyclicheteroaryl(C₁-C₃)alkyl, wherein the aromatic and heteroaromatic groupsare optionally substituted with 1 to 3 groups independently selectedfrom fluorine, chlorine, cyano, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)-alkoxy, (C₁-C₃)alkanesulfonyl, and(C₁-C₃)alkoxycarbonyl; G is OH, OR⁹, NH₂, NHR⁹, NR⁹R¹⁰, C(═NH)NH₂,C(═NH)NHR⁹, NHC(═NH)NH₂, or NHC(═NH)NHR⁹; R⁹ is a) (C₁-C₁₂)alkyl,(C₄-C₁₂)cycloalkylalkyl, halo(C₁-C₁₂)alkyl, halo(C₄-C₁₂)cycloalkylalkyl,(C₂-C₁₂)alkenyl, (C₅-C₁₂)cycloalkylalkenyl, halo(C₂-C₁₂)alkenyl,halo(C₅-C₁₂)cycloalkyl alkenyl, (C₂-C₁₂)alkynyl,(C₅-C₁₂)cycloalkylalkynyl, halo(C₂-C₁₂)alkynyl,halo(C₅-C₁₂)cycloalkylalkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl,halo(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₆)alkane-sulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₆)alkanesulfonyl(C₁-C₆)alkyl, aminocarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylamino-carbonyl(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, saturatedheterocyclyl, or saturated heterocyclyl(C₁-C₆)alkyl or b) phenyl,naphthyl, heteroaryl, phenyl(C₁-C₃)alkyl, naphthyl(C₁-C₃)alkyl, orheteroaryl(C₁-C₃)alkyl, each optionally substituted by 1 to 3 groupsindependently selected from: 1) fluorine, chlorine, bromine, iodine,cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl-(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkane-sulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)-cycloalkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl,cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkoxy(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkoxy(C₁-C₆)alkyl, (C₁-C₈)alkylthio(C₁-C₆)alkyl,(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkylthio(C₁-C₆)alkyl,halo(C₁-C₈)alkylthio(C₁-C₆)alkyl, halo(C₃-C₈)cycloalkythio(C₁-C₆)alkyl,halo(C₄-C₈)-cycloalkylalkylthio(C₁-C₆)alkyl,(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,(C₃-C₈)-cycloalkanesulfinyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkyl-alkanesulfinyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfinyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfinyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkanesulfinyl(C₁-C₆)alkyl,(C₁-C₈)alkane-sulfonyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,(C₄-C₈)cycloalkylalkanesulfonyl(C₁-C₆)alkyl,halo(C₁-C₈)alkanesulfonyl(C₁-C₆)alkyl,halo(C₃-C₈)cycloalkanesulfonyl(C₁-C₆)alkyl,halo(C₄-C₈)cycloalkylalkane-sulfonyl(C₁-C₆)alkyl,(C₁-C₈)alkylamino(C₁-C₆)alkyl, di(C₁-C₈)alkylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₈)acyloxy(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carbonyl(C₁-C₆)alkyl,di(C₁-C₈)alkylaminocarbonyl(C₁-C₆)alkyl (C₁-C₈)acylamino(C₁-C₆)alkyl,(C₁-C₈)alkoxycarbonylamino, (C₁-C₈)alkoxycarbonylamino(C₁-C₆)alkyl,aminocarboxy(C₁-C₆)alkyl, (C₁-C₈)alkylamino-carboxy(C₁-C₆)alkyl anddi(C₁-C₈)alkylaminocarboxy(C₁-C₆)alkyl; or 2) phenyl, napthyl,heteroaryl, bicyclic heteroaryl, phenoxy, naphthyloxy, heteroaryloxy,bicyclic heteroaryloxy, phenylthio, naphthylthio, heteroarylthio,bicyclic heteroarylthio, phenylsulfinyl, naphthylsulfinyl,heteroarylsulfinyl, bicyclic heteroarylsulfinyl, phenylsulfonyl,naphthylsulfonyl, heteroarylsulfonyl, bicyclic heteroarylsulfonyl,phenyl(C₁-C₃)alkyl, napthyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, andbicyclic heteroaryl(C₁-C₃)alkyl, each optionally substituted with 1 to 3groups independently selected from fluorine, chlorine, cyano,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy,(C₁-C₃)alkanesulfonyl, and (C₁-C₃)-alkoxycarbonyl; or b) R⁹ is asaturated divalent radical composed of carbon atoms, and 0, 1 or 2hetero atoms selected from 0 or 1 nitrogen atoms, 0 or 1 oxygen atoms,and 0 or 1 sulfur atoms that is attached to any core carbon atom on L toform a saturated 3-, 4-, 5-, 6-, or 7-membered L-G ring; said L-G ringbeing optionally substituted with 1 to 4 groups selected from halogen,fluorine, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,halo(C₃-C₈)cycloalkyl, hydroxy(C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkyl, halo(C₃-C₈)cycloalkyl(C₁-C₃)alkyl,hydroxylated (C₃-C₈)cycloalkyl(C₁-C₃)alkyl, (C₁-C₈)alkoxy,halo(C₁-C₈)alkoxy, (C₃-C₈)cycloalkoxy, halo(C₃-C₈)cycloalkoxy,hydroxy(C₃-C₈)cycloalkoxy, (C₁-C₈)alkoxy(C₁-C₃)alkyl,halo(C₁-C₈)alkoxy(C₁-C₃)alkyl, (C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkoxy(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₁-C₈)alkylthio, halo(C₁-C₈)alkylthio, (C₃-C₈)cycloalkylthio,halo(C₃-C₈)cycloalkylthio, hydroxy(C₃-C₈)cycloalkylthio,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio,(C₁-C₈)alkylthio(C₁-C₃)alkyl, halo(C₁-C₈)alkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,hydroxy(C₃-C₈)cycloalkylthio(C₁-C₃)alkyl,(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,halo(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl,hydroxylated(C₃-C₈)cycloalkyl(C₁-C₃)alkylthio(C₁-C₃)alkyl and oxo; R¹⁰is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; provided that when R² is(C₁-C₁₂)alkyl and R³ is OH, only a single substituent R⁵ is allowed onL; or an enantiomer, diastereomer or pharmaceutically acceptable saltthereof.
 39. A compound of Formula I

wherein R¹ is a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl,3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl,4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl,7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyloptionally substituted with 1 to 3 substituents independently selectedfrom: fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl,t-butyl, isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1-yl,cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio,allyloxy, cyclopropylmethoxy, 2-(cyclopropyl)ethoxy, cyclopentyloxy,cyclopentylmethoxy, benzyloxy, hydroxyl, aminocarbonyl, methoxycarbonyl,phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenylphenoxy, benzyloxy and heteroaryloxy groups are optionally substitutedwith 1 to 3 substituents independently selected from fluorine, chlorine,cyano, methyl, ethyl, trifluoromethyl, and aminocarbonyl; X and Y iseach a single bond; R² is methyl, ethyl, propyl, butyl, pentyl, hexyl,5-pentenyloxy, 3,3,3-trifluoropropyl, 4,4-difluoropentyl,3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl,4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl,2-hydroxyethoxy, 3-methoxypropyl, 3-ethoxypropyl, 4-methoxybutyl,4-ethoxybutyl, 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,3-propoxypropoxy, 2-cyclopropylethoxy, (2-(methoxy)ethoxy)methyl,3-(acetylamino)propyl, 3-(propionylamino)propyl,3-(butanoylamino)propyl, 3-((2-methoxypropionyl)amino)propyl,3-(cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl,3-(methylaminocarbonylamino)propyl,3-(dimethylaminocarbonylamino)propyl, 2-(acetylamino)ethoxy,2-(propionylamino)ethoxy, methoxymethylcarbonylaminomethyl,3-(aminosulfonylamino)propyl or 3-(methanesulfonylamino)propyl; R³ is H,F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino,(2-methylpropionyl)amino, or butanoylamino, provided that when R³ is For OH, R² is not 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,3-propoxypropoxy, 2-cyclopropylethoxy, 2-(acetylamino)ethoxy or2-(propionylamino)ethoxy; A is 2,4-disubstituted morpholine withR¹XCR²R³Y attached at the 2-position and Q attached at the 4-position,1,3-disubstituted piperidine with R¹XCR²R³Y attached at the 3-positionand Q attached at the 1-position, 1,3-disubstituted-3-methylpiperidinewith R¹XCR²R³Y attached at the 3-position and Q attached at the1-position, 1,3-disubstituted benzene, or 1,3-disubstituted cyclohexane;Q is Q1, Q2, Q4, Q5, Q9, or Q10

R⁴ is H or methyl; L is a C₂ alkyl chain in which one hydrogen atom isoptionally replaced with a group selected from R⁵; R⁵ is methyl,isobutyl, t-butylmethyl, 2,2,2-trifluoroethyl,2-(trifluoromethyl)propyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-(cyclohexyl)ethyl, (3-noradamantyl)methyl,(3,3-difluorocyclobutyl)methyl, (3,4-difluorocyclopentyl)methyl,4,4-difluorocyclohexylmethyl, (4-methylcyclohexyl)methyl,tert-butoxymethyl, (2-tetrahydrofuranyl)methyl,(2-tetrahydropyranyl)methyl, (4-tetrahydropyranyl)methyl,(3-methoxycyclobutyl)methyl, (4-methoxycyclohexyl)methyl, benzyl,phenethyl, (1-fluorocyclohexyl)methyl, (4-fluorocyclohexyl)methyl,1-hydroxy-2-methylpropyl, (cyclopentyl)(hydroxy)methyl,(cyclohexyl)(hydroxy)methyl, (4-fluorocyclohexyl)(hydroxy)methyl,(cycloheptyl)(hydroxy)methyl, (1-hydroxycyclohexyl)methyl,(4-hydroxycyclohexyl)methyl, (4-hydroxy-4-methylcyclohexyl)methyl,(3-noradamantyl)(hydroxy)methyl, 2-methoxy-2-methylpropyl, or2,2-dimethyl-3-methoxypropyl; R⁶ is absent or is methyl orhydroxymethyl; R⁷ and R⁸ are absent; G is NH₂, NHR⁹, or NR⁹R¹⁰; R⁹ ismethyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl,aminocarbonylmethyl, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₂CH(c-hex)-, or—(CH₂)₂CH(OCH(C₂H₅)₂)—; R¹⁰ is methyl; provided that when R² is methyl,ethyl, propyl, butyl, pentyl or hexyl and R³ is OH, R⁶ is absent; or anenantiomer, diastereomer or pharmaceutically acceptable salt thereof.40. A pharmaceutical composition comprising a compound of any one ofclaims 31 to 39, or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.